MaltSci 麦伴科研

Appearance

Popular Reports / Immunology

This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of autoimmune diseases? ​

Abstract ​

Autoimmune diseases represent a complex array of disorders characterized by the immune system's inappropriate attack on the body's own tissues, affecting approximately 10% of the global population. The pathogenesis of these diseases is multifactorial, involving genetic predispositions, environmental triggers, and dysregulated immune responses. Recent advances in immunology have shed light on the roles of autoreactive T and B cells, cytokine signaling, and environmental factors such as infections and dietary components in the onset and progression of autoimmunity. Genetic factors, including specific human leukocyte antigen (HLA) variants, significantly influence susceptibility to autoimmune diseases, while environmental factors can act as triggers that disrupt immune tolerance. The interplay between genetic and environmental factors is further complicated by epigenetic modifications that alter gene expression without changing the DNA sequence, thus contributing to the pathogenesis of autoimmune conditions. The review synthesizes current knowledge on the mechanisms of autoimmunity, emphasizing the need for targeted therapeutic strategies aimed at restoring immune balance. Emerging therapies, including biologics and antigen-specific immunotherapies, offer promising avenues for more effective treatment of these complex disorders. Future research directions include a focus on personalized medicine approaches that consider individual genetic and environmental profiles to improve patient outcomes.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Mechanisms of Autoimmunity
    • 2.1 Genetic Factors in Autoimmune Diseases
    • 2.2 Environmental Triggers and Their Role
    • 2.3 Dysregulation of Immune Responses
    • 2.4 The Role of Autoreactive Lymphocytes
  • 3 Cytokine Signaling in Autoimmunity
    • 3.1 Pro-inflammatory Cytokines
    • 3.2 Anti-inflammatory Cytokines and Their Impact
    • 3.3 Cytokine Networks in Disease Progression
  • 4 Microbiome and Autoimmune Diseases
    • 4.1 Gut Microbiota and Immune Regulation
    • 4.2 Microbial Antigens and Autoimmunity
    • 4.3 Therapeutic Potential of Microbiome Modulation
  • 5 Current and Emerging Therapies
    • 5.1 Conventional Treatment Approaches
    • 5.2 Novel Therapeutics Targeting Immune Mechanisms
    • 5.3 Future Directions in Autoimmune Therapy
  • 6 Challenges and Future Perspectives
    • 6.1 Gaps in Current Research
    • 6.2 The Importance of Personalized Medicine
    • 6.3 Strategies for Improving Patient Outcomes
  • 7 Conclusion

1 Introduction ​

Autoimmune diseases are a diverse and complex group of disorders characterized by the immune system's aberrant attack on the body's own tissues. This phenomenon can lead to a range of conditions, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes, which collectively affect approximately 10% of the global population [1]. The pathogenesis of these diseases is multifactorial, involving intricate interactions among genetic predispositions, environmental triggers, and dysregulated immune responses [2]. Understanding the underlying mechanisms of autoimmunity is not only essential for elucidating the pathophysiology of these disorders but also for developing effective therapeutic strategies aimed at restoring immune tolerance and improving patient outcomes [3].

The significance of researching autoimmune diseases is underscored by their increasing prevalence and the substantial burden they impose on healthcare systems worldwide [1]. The intricate interplay of various factors that contribute to the onset and progression of autoimmune conditions necessitates a comprehensive understanding of their mechanisms. Recent advances in immunology and molecular biology have provided insights into the roles of autoreactive T and B cells, the influence of cytokines, and the impact of environmental factors, including microbial interactions [2][4]. Moreover, emerging research on epigenetic modifications highlights additional layers of complexity in the regulation of immune responses [5].

Current literature emphasizes the necessity of examining both genetic and environmental influences on autoimmunity. Genetic predispositions, such as specific human leukocyte antigen (HLA) variants, have been linked to various autoimmune diseases [6]. Concurrently, environmental factors, including infections, chemical exposures, and lifestyle choices, play critical roles in triggering autoimmune responses in genetically susceptible individuals [7]. The hygiene hypothesis, for instance, posits that reduced exposure to pathogens may contribute to an increased incidence of autoimmune diseases by impairing the development of immune tolerance [8].

This review aims to synthesize current knowledge regarding the mechanisms of autoimmune diseases, organized into several key sections. The first section will delve into the genetic factors associated with autoimmune diseases, exploring how specific genetic variants predispose individuals to these conditions. Following this, we will examine the environmental triggers that contribute to the breakdown of immune tolerance, highlighting the roles of infections and other external factors. The third section will focus on the dysregulation of immune responses, discussing how alterations in immune cell populations can lead to autoimmunity. The role of autoreactive lymphocytes will be addressed next, elucidating the mechanisms through which these cells contribute to tissue damage.

Subsequent sections will explore the role of cytokine signaling in autoimmune diseases, detailing the functions of both pro-inflammatory and anti-inflammatory cytokines in disease progression. The relationship between the microbiome and autoimmunity will also be examined, particularly the ways in which gut microbiota influence immune regulation and contribute to disease pathogenesis. Current and emerging therapeutic strategies will be discussed, including conventional treatment approaches and novel therapeutics targeting immune mechanisms. Finally, we will address the challenges and future perspectives in autoimmune disease research, identifying gaps in current knowledge and emphasizing the importance of personalized medicine in improving patient outcomes.

By integrating insights from recent studies and highlighting critical areas for future research, this review seeks to enhance our understanding of the complex mechanisms underlying autoimmune diseases and to inform the development of targeted interventions.

2 Mechanisms of Autoimmunity ​

2.1 Genetic Factors in Autoimmune Diseases ​

Autoimmune diseases are characterized by a complex interplay of genetic, epigenetic, and environmental factors that contribute to the loss of self-tolerance and the subsequent immune response against self-antigens. The mechanisms underlying these diseases are multifaceted and can be categorized into several key areas.

Genetic factors play a crucial role in the predisposition to autoimmune diseases. Research indicates that genetic susceptibility is significant, as evidenced by the higher concordance rates of autoimmune diseases in monozygotic twins compared to dizygotic twins. However, even monozygotic twins can exhibit discordance for autoimmune diseases, highlighting the influence of environmental factors alongside genetic predisposition (Dang et al. 2013). Specific genetic variants have been identified through genetic mapping, which has pinpointed candidate genes associated with various autoimmune conditions. For instance, molecules involved in antigen recognition and immune signaling, such as major histocompatibility complex (MHC) molecules, are crucial in determining susceptibility to autoimmune diseases (Houen 2024).

Epigenetic mechanisms also play a significant role in the development of autoimmune diseases. Epigenetics refers to heritable changes in gene expression that do not involve alterations to the DNA sequence itself. The primary mechanisms of epigenetic regulation include DNA methylation, histone modifications, and non-coding RNA-mediated regulation. These mechanisms can modulate gene expression in response to environmental stimuli, thus influencing the immune response (Wu et al. 2016). For example, in type 1 diabetes, DNA methylation and histone modifications have been linked to altered gene expression, suggesting that epigenetic changes may be pivotal in disease pathogenesis (Ngoc Dang et al. 2013).

The interaction between genetic and epigenetic factors is crucial in understanding autoimmune diseases. Environmental factors, such as infections, pollutants, and dietary components, can trigger epigenetic modifications that may lead to the activation of autoimmune processes. This interplay suggests that while genetic factors provide a predisposition to autoimmune diseases, environmental influences can activate these predispositions through epigenetic changes (Aslani et al. 2016).

Additionally, hormonal factors, particularly in females, have been shown to influence the incidence of autoimmune diseases. Gender differences in immune response and hormonal regulation may account for the higher prevalence of certain autoimmune diseases in women, such as systemic lupus erythematosus (Rubtsov et al. 2010).

The role of environmental factors cannot be overstated. Infections, particularly viral infections like Epstein-Barr virus, have been strongly associated with the development of autoimmune diseases such as multiple sclerosis (Houen 2024). Environmental agents can induce epigenetic changes that may trigger autoimmunity in genetically susceptible individuals, emphasizing the importance of the environment in the pathogenesis of these diseases (García-Carrasco et al. 2009).

In summary, the mechanisms of autoimmune diseases are complex and involve a combination of genetic predisposition, epigenetic modifications, and environmental triggers. Understanding these interactions is critical for developing effective therapeutic strategies and interventions aimed at preventing and treating autoimmune diseases.

2.2 Environmental Triggers and Their Role ​

The mechanisms leading to autoimmune diseases are complex and multifactorial, involving an interplay of genetic predisposition, environmental factors, and immune regulation. Environmental triggers have gained significant attention for their role in the induction and perpetuation of autoimmunity. Various studies highlight several key mechanisms through which environmental factors can influence the onset of autoimmune diseases.

One prominent mechanism is molecular mimicry, where environmental agents such as infections can induce an immune response that mistakenly targets self-antigens due to structural similarities between microbial and host proteins. This phenomenon is notably implicated in conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis, where infections, particularly viral and bacterial, can trigger or exacerbate autoimmune responses [9][10].

Additionally, epitope spreading occurs when an initial immune response to a specific antigen leads to the activation of T and B cells against other self-antigens, thereby expanding the autoimmune response. This process can be facilitated by environmental factors that alter the immune landscape, such as changes in gut microbiota or exposure to chemicals [7][11].

Bystander activation is another critical mechanism, where non-specific activation of immune cells occurs in the context of inflammation caused by environmental triggers. This can lead to the activation of autoreactive lymphocytes that were previously inert, contributing to the development of autoimmune diseases [7].

The role of innate immunity is also essential in the context of environmentally induced autoimmunity. Studies indicate that innate immune pathways, particularly those mediated by toll-like receptors (TLRs), are crucial in the initiation of autoimmune responses. For instance, TLR signaling can differentiate between various types of immune responses, influencing whether an autoimmune pathology develops [12].

Moreover, epigenetic changes induced by environmental exposures, such as DNA methylation and histone modifications, can alter gene expression patterns without changing the DNA sequence itself. These epigenetic modifications may lead to the breakdown of immune tolerance and the subsequent development of autoimmunity [6].

Chemical exposures, including xenobiotics, have been linked to autoimmune diseases, with mechanisms involving inflammation and the innate immune response. Environmental factors like drugs, chemicals, and heavy metals can trigger autoimmune reactions by causing localized tissue damage and chronic inflammation, which release self-antigens and promote autoreactive immune responses [13].

In summary, the mechanisms of autoimmune diseases are influenced by a variety of environmental triggers that interact with genetic predispositions and immune regulatory pathways. These interactions can lead to the breakdown of self-tolerance and the activation of autoreactive immune responses through mechanisms such as molecular mimicry, epitope spreading, bystander activation, and epigenetic modifications, underscoring the complexity of autoimmune disease pathogenesis.

2.3 Dysregulation of Immune Responses ​

Autoimmune diseases arise from a complex interplay of genetic, environmental, and immunological factors, resulting in inappropriate immune responses against self-antigens. A fundamental aspect of these disorders is the dysregulation of immune responses, which can be understood through several mechanisms.

Firstly, autoimmune diseases are characterized by an imbalance between effector and regulatory immune responses. This dysregulation often leads to the survival and activation of autoreactive lymphocytes, which target the body’s own tissues. The mechanisms underlying this imbalance include defects in central tolerance, where autoreactive T and B cells are typically eliminated during their development. In normal conditions, regulatory T cells (Tregs) and various immune checkpoints, such as CTLA-4 and IL-10, help to suppress these autoreactive cells that escape negative selection. However, in autoimmune conditions, this regulatory mechanism fails, resulting in uncontrolled immune activation and subsequent tissue damage [3].

Another critical mechanism involves epigenetic modifications that influence gene expression without altering the DNA sequence. These modifications can affect immune cell function and contribute to the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The role of epigenetic dysregulation suggests that environmental factors, such as infections or toxins, may trigger changes in gene expression that predispose individuals to autoimmune responses [14].

Moreover, the metabolic state of immune cells plays a significant role in autoimmunity. Dysregulated immunometabolism, particularly in B cells, can lead to abnormal activation and production of autoantibodies. Metabolic pathways provide the necessary energy and substrates for immune cell activation and function, and alterations in these pathways can disrupt self-tolerance mechanisms, further contributing to autoimmune disease [15].

Environmental triggers also significantly impact the development of autoimmune diseases. Factors such as infections, hormonal changes, and dietary influences can initiate or exacerbate autoimmune responses in genetically susceptible individuals. For instance, the presence of certain pathogens can mimic self-antigens, leading to a phenomenon known as molecular mimicry, which may trigger an autoimmune response [16].

In addition to these factors, genetic predisposition plays a crucial role in determining susceptibility to autoimmune diseases. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with various autoimmune conditions, highlighting the involvement of specific genes in regulating immune responses and maintaining self-tolerance [17].

In summary, the mechanisms of autoimmune diseases are multifaceted, involving dysregulation of immune responses, epigenetic changes, metabolic alterations, environmental triggers, and genetic predisposition. Understanding these mechanisms is essential for developing targeted therapeutic strategies to restore immune balance and mitigate the effects of autoimmune diseases.

2.4 The Role of Autoreactive Lymphocytes ​

Autoimmune diseases arise from a breakdown of physiological mechanisms that maintain tolerance to self-antigens, leading to the activation and proliferation of autoreactive lymphocytes. These lymphocytes, which include both T and B cells, play a central role in the pathogenesis of autoimmune disorders.

The mechanisms underlying autoimmunity can be categorized into central and peripheral tolerance. Central tolerance occurs during lymphocyte development in primary lymphoid organs, such as the thymus and bone marrow, where autoreactive lymphocytes are deleted or rendered unresponsive. However, this process is not perfect, allowing some autoreactive cells to escape into the periphery [18]. Peripheral tolerance mechanisms, which include anergy, apoptosis, and suppression by regulatory T cells (Tregs), are crucial for maintaining immune homeostasis and preventing autoimmunity. When these mechanisms fail, autoreactive lymphocytes can become activated, leading to tissue damage and autoimmune disease [19].

The role of autoreactive T and B lymphocytes is pivotal in the progression from autoimmunity to autoimmune disease. T lymphocytes can directly attack self-tissues, while B lymphocytes contribute by producing autoantibodies that target self-antigens. The activation of these lymphocytes is influenced by various factors, including genetic predispositions and environmental triggers, such as infections. The interplay between these factors can lead to the activation of autoreactive lymphocytes, resulting in the onset of autoimmune pathology [20].

Recent studies have highlighted the importance of innate lymphocytes in autoimmune diseases. These cells can respond rapidly to antigens and are involved in amplifying or attenuating immune responses. They may contribute to the maintenance of autoimmune processes through their cytotoxic effects, leading to tissue damage [20]. Furthermore, the dysregulation of metabolic pathways in lymphocytes has been implicated in the pathogenesis of autoimmune diseases. Metabolic reprogramming of these cells can influence their function and contribute to the development of autoimmunity [21].

The initiation of autoimmune diseases often requires a combination of factors, including genetic susceptibility, the presence of naive lymphocytes capable of reacting with autoantigens, and precipitating events that activate these cells [22]. In this context, infections have been proposed as potential triggers, as they may expose autoreactive T cells to cross-reactive peptides, a phenomenon known as molecular mimicry [23].

Overall, the mechanisms of autoimmune diseases are complex and involve the interplay of autoreactive lymphocytes, regulatory pathways, and environmental factors. Understanding these mechanisms is essential for developing targeted therapeutic strategies to treat and prevent autoimmune disorders.

3 Cytokine Signaling in Autoimmunity ​

3.1 Pro-inflammatory Cytokines ​

Autoimmune diseases are characterized by dysregulated adaptive immune responses, which lead to chronic inflammation and tissue damage. Central to the pathogenesis of these diseases are cytokines, which are signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis. The mechanisms involved in autoimmune diseases often hinge on an imbalance between pro-inflammatory and anti-inflammatory cytokines.

Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-17 (IL-17), and interferon-gamma (IFN-γ), play pivotal roles in the initiation and propagation of autoimmune inflammation. For instance, TNF-α is a key mediator in the inflammatory processes associated with diseases like rheumatoid arthritis, Crohn's disease, and psoriasis. It is known to induce a variety of inflammatory responses, including the activation of endothelial cells, promotion of leukocyte adhesion, and stimulation of other pro-inflammatory cytokines [24].

IL-17, produced primarily by T-helper 17 (Th17) cells, is particularly important in the context of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. This cytokine contributes to the recruitment of neutrophils and macrophages to sites of inflammation, amplifying the immune response and perpetuating the cycle of inflammation [25]. Moreover, the IL-23/IL-17 axis has emerged as a critical pathway in the pathogenesis of autoimmune conditions, emphasizing the importance of Th17 cells in driving inflammatory processes [25].

Cytokines also participate in creating feedback loops that sustain chronic inflammation. For example, excessive signaling through the IL-1β pathway has been implicated in various autoinflammatory syndromes, leading to the production of additional pro-inflammatory cytokines and the perpetuation of inflammatory cycles [26]. Furthermore, the interplay between pro-inflammatory and anti-inflammatory cytokines, such as IL-10 and IL-4, is crucial in maintaining immune homeostasis. Dysregulation of these cytokines can result in the breakdown of tolerance and the emergence of autoreactive lymphocytes, contributing to autoimmune pathology [19].

The signaling pathways activated by these cytokines, including the JAK-STAT and NF-κB pathways, are integral to the development of autoimmune diseases. Aberrant activation of these pathways can lead to altered gene expression profiles that favor inflammation and autoimmunity [27]. The complexity of cytokine signaling, characterized by overlapping effects and interactions, poses challenges in delineating the precise contributions of individual cytokines to the pathogenesis of specific autoimmune disorders [28].

In summary, the mechanisms underlying autoimmune diseases are multifaceted and involve a delicate balance between pro-inflammatory and anti-inflammatory cytokines. The dysregulation of these cytokines, their signaling pathways, and the resultant chronic inflammatory responses are central to the pathogenesis of autoimmune diseases, underscoring the potential of targeting cytokine signaling as a therapeutic strategy in managing these conditions [29][30].

3.2 Anti-inflammatory Cytokines and Their Impact ​

Autoimmune diseases are characterized by dysregulated immune responses that lead to chronic inflammation and tissue damage. The pathogenesis of these conditions is complex and involves a multitude of mechanisms, with cytokines playing a pivotal role. Cytokines are small secreted proteins that facilitate communication between immune cells and are crucial in regulating immune responses. Their dual nature means they can be both pro-inflammatory and anti-inflammatory, influencing the progression of autoimmune diseases in different ways.

Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-17 (IL-17), and interferon-gamma (IFN-γ), are often elevated in autoimmune conditions. These cytokines contribute to the initiation and propagation of inflammation, leading to tissue damage and the exacerbation of autoimmune responses. For instance, TNF-α has been implicated in diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), where it drives the inflammatory process and perpetuates tissue injury [29].

On the other hand, anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), play essential roles in regulating immune tolerance and resolving inflammation. These cytokines can counteract the effects of pro-inflammatory cytokines, promoting healing and tissue repair. In the context of autoimmune diseases, a deficiency or dysfunction in anti-inflammatory cytokines can lead to uncontrolled inflammation and disease progression [30].

The balance between pro-inflammatory and anti-inflammatory cytokines is critical for maintaining immune homeostasis. Disruption of this balance can result from various factors, including genetic predispositions, environmental triggers, and dysregulation of immune cell signaling pathways. For example, the IL-17/IL-23 axis has emerged as a significant pathway in autoimmune pathology, particularly in conditions like multiple sclerosis (MS) and psoriasis, where the overproduction of IL-17 contributes to inflammatory processes [25].

Moreover, the signaling pathways activated by cytokines, such as the JAK-STAT pathway, are crucial for mediating the effects of these cytokines on immune cells. Dysregulation of these pathways can lead to aberrant immune responses, further exacerbating autoimmune conditions [27]. Advances in understanding these mechanisms have opened new avenues for therapeutic interventions, such as anti-cytokine therapies that aim to restore the balance of cytokine signaling and mitigate the inflammatory response [31].

In summary, the mechanisms underlying autoimmune diseases are multifaceted, with cytokine signaling playing a central role. The interplay between pro-inflammatory and anti-inflammatory cytokines determines the nature and severity of the immune response. Understanding these dynamics is essential for developing targeted therapies aimed at restoring immune balance and improving patient outcomes in autoimmune diseases.

3.3 Cytokine Networks in Disease Progression ​

Autoimmune diseases are characterized by the immune system's inappropriate response against the body's own tissues, leading to inflammation and tissue damage. The mechanisms underlying these diseases are complex and multifactorial, with cytokines playing a crucial role in their pathogenesis and progression.

Cytokines are small secreted proteins that facilitate communication between immune cells and are pivotal in regulating immune responses. They can be classified into pro-inflammatory and anti-inflammatory cytokines, each contributing differently to the immune landscape in autoimmune diseases. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-17 (IL-17) are often elevated in autoimmune conditions and are involved in the initiation and perpetuation of inflammatory responses [28][29][32].

The imbalance between pro-inflammatory and anti-inflammatory cytokines is a hallmark of autoimmune diseases. For instance, in rheumatoid arthritis (RA), a chronic inflammatory condition, the action of pro-inflammatory cytokines contributes to joint inflammation and damage. Conversely, anti-inflammatory cytokines play a role in resolving inflammation and restoring homeostasis. The intricate interplay between these cytokines determines the disease course and severity [19][32].

Cytokine signaling is mediated through specific receptors on target cells, leading to the activation of intracellular signaling pathways such as the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Dysregulation of these pathways can result in aberrant immune responses and contribute to autoimmune pathology [33]. For example, the IL-17/IL-23 axis has been identified as a critical pathway in the pathogenesis of autoimmune diseases, particularly in conditions like multiple sclerosis (MS) and inflammatory bowel disease (IBD) [25].

Moreover, the cytokine milieu, or the collective presence and interaction of various cytokines, can sustain chronic inflammation in autoimmune diseases. This network of cytokines creates a feedback loop that can exacerbate tissue damage and disease progression. The complexity of these interactions poses significant challenges for therapeutic interventions aimed at targeting specific cytokines, as the effects of such treatments can be unpredictable due to the overlapping and often compensatory roles of different cytokines [19][34].

In summary, the mechanisms of autoimmune diseases involve a delicate balance of cytokine signaling that regulates immune responses. The disruption of this balance, characterized by an excess of pro-inflammatory cytokines and impaired regulatory mechanisms, leads to the pathogenesis of autoimmune disorders. Understanding these mechanisms is crucial for developing targeted therapies that can effectively modulate cytokine networks and improve patient outcomes [19][29].

4 Microbiome and Autoimmune Diseases ​

4.1 Gut Microbiota and Immune Regulation ​

Autoimmune diseases arise from a complex interplay of genetic, environmental, and immunological factors, with the gut microbiota playing a significant role in the regulation of immune responses. The gut microbiota is essential for maintaining immune homeostasis, influencing both local and systemic immune functions. Dysbiosis, or an imbalance in the gut microbiota composition, has been implicated in the pathogenesis of various autoimmune diseases.

The mechanisms through which the gut microbiota influences autoimmune diseases are multifaceted. Firstly, gut microbes interact with the immune system by modulating the differentiation and function of immune cells. For instance, microbial metabolites can influence the expression of microRNAs, which in turn affects gene expression at the post-transcriptional level, impacting crucial immune functions such as lymphocyte differentiation and interleukin production [35]. Furthermore, gut microbiota can affect the permeability of the intestinal barrier. Disruption of this barrier allows bacteria and their metabolites to enter systemic circulation, potentially triggering autoimmune responses by activating or interfering with the immune system [36].

The gut microbiota also engages in antigenic mimicry, where microbial antigens resemble host antigens. This can lead to cross-reactivity, wherein autoreactive T cells mistakenly target self-tissues, contributing to the development of autoimmune diseases [37]. Additionally, the gut microbiota can influence the balance between pathogenic effector T cells and regulatory T cells (Tregs). An imbalance in these cell populations is a hallmark of autoimmune diseases, as it can lead to an overactive immune response against self-antigens [38].

Moreover, environmental factors, such as diet, can significantly influence the gut microbiota composition and its functional output. Dietary components can modulate microbial metabolism, which in turn impacts immune regulation. This suggests that dietary interventions may be a potential therapeutic strategy for managing autoimmune diseases [39].

In summary, the mechanisms underlying autoimmune diseases related to gut microbiota involve complex interactions that include immune modulation through microbial metabolites, disruption of the intestinal barrier, antigenic mimicry, and the influence of dietary factors on microbiome composition. Understanding these mechanisms is crucial for developing innovative treatment strategies aimed at restoring microbiome balance and improving immune tolerance in individuals predisposed to autoimmune conditions [40][41].

4.2 Microbial Antigens and Autoimmunity ​

Autoimmune diseases are complex, multifactorial disorders characterized by the immune system's failure to distinguish between self and non-self, leading to the attack on the body's own tissues. Recent research has highlighted the significant role of the microbiome in the pathogenesis of these diseases, suggesting that microbial antigens can influence autoimmune responses through various mechanisms.

One of the key mechanisms involves the concept of molecular mimicry, where microbial antigens share structural similarities with host self-antigens. This similarity can lead to cross-reactivity, where the immune system, upon encountering these microbial antigens, inadvertently targets self-tissues due to the resemblance. This phenomenon has been implicated in several autoimmune conditions, including rheumatic fever and type 1 diabetes, where infections with specific bacteria or viruses precede the onset of autoimmune responses [23].

Moreover, the dysbiosis of the gut microbiome has been associated with the development of autoimmune diseases. Dysbiosis refers to an imbalance in the microbial community, which can result from various factors such as diet, antibiotics, and infections. This imbalance can lead to an altered immune response, characterized by increased production of pro-inflammatory cytokines and changes in T cell differentiation. For instance, specific gut microbes can modulate the differentiation of T helper cells, including the promotion of autoreactive Th17 cells, which are known to play a crucial role in autoimmune pathogenesis [42].

The gut microbiota also influences the integrity of the gut barrier. A compromised gut barrier can allow the translocation of microbial antigens into the systemic circulation, further provoking autoimmune responses. In this context, the production of microbial metabolites, such as short-chain fatty acids, has been shown to have protective effects on gut permeability and immune regulation [35].

In addition to molecular mimicry and dysbiosis, the microbiome can affect the host's immune tolerance. The gut microbiota is essential for the development and maturation of the immune system, helping to establish tolerance to self-antigens. When the composition of the microbiome is disrupted, this tolerance can be lost, leading to autoimmune disease [43]. Furthermore, the interplay between the microbiome and host immune cells can influence the production of autoantibodies, as seen in conditions like Crohn's disease and Sjögren's syndrome, where anti-microbial antibodies exhibit cross-reactivity with self-antigens [44].

Recent studies have also explored the role of environmental factors and hormones in modulating the relationship between the microbiome and autoimmunity. For example, hormonal changes can influence the microbiota composition and, consequently, the immune response, particularly in diseases like rheumatoid arthritis and multiple sclerosis [45].

In summary, the mechanisms underlying autoimmune diseases are multifaceted, with microbial antigens playing a significant role in triggering and exacerbating these conditions. The interactions between the microbiome, immune system, and environmental factors contribute to the complex etiology of autoimmunity, highlighting the potential for microbiome-targeted therapies as a novel approach to managing these diseases [46].

4.3 Therapeutic Potential of Microbiome Modulation ​

Autoimmune diseases are complex multifactorial disorders characterized by an inappropriate immune response against the body's own tissues. The pathogenesis of these diseases involves a combination of genetic predisposition and environmental factors, including significant contributions from the gut microbiome. The mechanisms by which the microbiome influences autoimmune diseases are intricate and multifaceted, encompassing several key interactions between gut microbiota, the immune system, and various metabolic processes.

The gut microbiome plays a crucial role in the development and maturation of the immune system, maintaining immune homeostasis, and influencing systemic inflammatory responses. Dysbiosis, or an imbalance in the gut microbiota, has been implicated in the pathogenesis of several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and multiple sclerosis (MS). For instance, microbial dysbiosis can lead to local inflammatory conditions, which may further trigger systemic autoimmune responses. The gut microbes interact with the immune system through various mechanisms, such as the modulation of host microRNAs, which affects gene expression at the post-transcriptional level, and the production of microbial metabolites that engage with cellular receptors like TLRs (Toll-like receptors) and GPCRs (G protein-coupled receptors) [35].

In the context of multiple sclerosis, it has been observed that the gut microbiota composition in individuals with MS differs significantly from that of healthy controls. Specific microbial taxa may influence disease risk and progression, particularly through their metabolic products, such as short-chain fatty acids and tryptophan metabolites, which can modulate immune responses [47]. Moreover, genetic factors interact with gut microbiota and dietary inputs, creating a complex environment where the microbiome can act as a significant environmental modifier of autoimmune disease risk [47].

The interaction between the microbiome and the immune system is also influenced by hormonal factors, which can modulate immune responses and potentially exacerbate autoimmune conditions [45]. For example, estrogens have been shown to impact the immune system's activity, affecting the development and progression of autoimmune diseases [45].

Therapeutically, modulating the gut microbiome presents a promising avenue for managing autoimmune diseases. Interventions such as probiotics, prebiotics, dietary modifications, and fecal microbiota transplantation (FMT) have gained attention as potential treatments. FMT, in particular, has demonstrated efficacy in restoring altered gut microbiota composition and mediating immune responses in conditions like inflammatory bowel disease and other autoimmune disorders [48]. These microbiota-based interventions aim to restore a balanced microbiome, thereby promoting immune tolerance and reducing inflammation [48].

Furthermore, the identification of specific microbial signatures associated with autoimmune diseases may lead to the development of diagnostic biomarkers and personalized therapeutic strategies [39]. Understanding the mechanisms through which the gut microbiome influences autoimmune diseases not only provides insights into disease pathogenesis but also opens up new avenues for targeted interventions that could mitigate the impact of these complex disorders [43].

In summary, the mechanisms underlying autoimmune diseases are deeply intertwined with gut microbiota dynamics, genetic predispositions, and environmental factors. The therapeutic potential of microbiome modulation holds promise for developing innovative strategies to prevent and treat autoimmune diseases, emphasizing the need for personalized approaches that consider individual microbiome compositions and responses to dietary interventions.

5 Current and Emerging Therapies ​

5.1 Conventional Treatment Approaches ​

Autoimmune diseases are characterized by the immune system's aberrant response against the body's own tissues, leading to chronic inflammation, tissue damage, and systemic dysfunction. The pathogenesis of these diseases is multifactorial, involving a complex interplay of genetic predisposition, environmental triggers, and dysregulated immune responses.

Genetic factors, such as variants in human leukocyte antigen (HLA) genes, are critical in determining susceptibility to autoimmune diseases. Approximately 10% of the global population is affected by these disorders, which impose significant health and economic burdens worldwide (Song et al., 2025) [1]. Additionally, environmental factors, including infections, smoking, and diet, can act as triggers or modifiers of autoimmune conditions, suggesting that the incidence of these diseases is influenced by both genetic and environmental components (Vorobyev & Ludwig, 2023) [49].

The mechanisms underlying autoimmune diseases can be further elucidated through various immunological concepts. Dysregulation of immune tolerance, which normally prevents autoreactive T and B cells from attacking self-tissues, plays a pivotal role. Central tolerance mechanisms eliminate most autoreactive lymphocytes during development; however, failures in these processes can lead to the survival of autoreactive cells in the periphery (Yang et al., 2018) [3]. Factors such as regulatory T cells (Tregs), cytokines like IL-10, and checkpoints like CTLA-4 are essential for maintaining tolerance and preventing autoimmunity. A breakdown in these regulatory mechanisms can result in the development of autoimmune diseases (Yang et al., 2018) [3].

Recent advancements have highlighted the role of metabolic reprogramming in autoimmune diseases. Aberrant metabolic pathways can contribute to the pathogenesis of conditions like type 1 diabetes and systemic lupus erythematosus (Jeong et al., 2023) [50]. Furthermore, epigenetic modifications, such as alterations in DNA methylation and histone modifications, are emerging as significant factors that may perpetuate autoreactive responses by disrupting immune tolerance (Ahmadi et al., 2017) [4].

In terms of conventional treatment approaches, the current therapeutic landscape primarily involves non-specific immunomodulators, including corticosteroids and immunosuppressants. While these treatments can alleviate symptoms and reduce inflammation, they often lead to significant side effects, including increased susceptibility to infections and other complications (Song et al., 2024) [51]. Therefore, there is a pressing need for more targeted therapies that can modulate the immune response without broad immunosuppression.

Emerging therapies focus on antigen-specific strategies aimed at restoring immune tolerance. These include the development of peptide vaccines designed to induce tolerance to specific autoantigens, thereby mitigating the autoimmune response without compromising the overall immune defense (Yu et al., 2023) [52]. Additionally, advances in nanotechnology are paving the way for nanovaccines that can enhance the delivery and efficacy of therapeutic agents targeting autoimmune diseases (Tang & Li, 2024) [53].

In conclusion, the mechanisms of autoimmune diseases involve a combination of genetic, environmental, and immunological factors leading to a breakdown of self-tolerance. Current treatments largely focus on non-specific immunosuppression, which poses risks for patients. However, ongoing research into more precise, targeted therapies holds promise for more effective management of these complex conditions.

5.2 Novel Therapeutics Targeting Immune Mechanisms ​

Autoimmune diseases are characterized by an aberrant immune response where the body's immune system mistakenly targets its own tissues, leading to chronic inflammation and tissue damage. The mechanisms underlying these diseases are complex and multifactorial, involving genetic predispositions, environmental triggers, and dysregulated immune responses.

The pathogenesis of autoimmune diseases often begins with a breakdown of immune tolerance, which is crucial for distinguishing self from non-self. Central and peripheral tolerance mechanisms normally eliminate self-reactive T and B cells. When these mechanisms fail, autoreactive lymphocytes become activated, producing antibodies that target the body's own tissues, resulting in various autoimmune disorders [19].

Recent research has identified several key mechanisms contributing to the initiation and progression of autoimmunity. These include:

  1. Genetic Factors: Specific genetic variants, particularly those related to human leukocyte antigen (HLA) genes, have been implicated in autoimmune diseases. These genetic predispositions can increase susceptibility to conditions like rheumatoid arthritis and systemic lupus erythematosus [1].

  2. Environmental Triggers: Factors such as infections, exposure to certain chemicals, and even dietary components can trigger autoimmune responses in genetically susceptible individuals. For instance, molecular mimicry, where pathogens share structural similarities with host tissues, can lead to cross-reactive immune responses [1].

  3. Cytokine Dysregulation: Pro-inflammatory cytokines play a significant role in the pathogenesis of autoimmune diseases. The imbalance between pro-inflammatory and anti-inflammatory cytokines can exacerbate autoimmune conditions. For example, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are critical mediators that have been targeted in therapeutic interventions [54].

  4. Apoptosis and Immune Cell Regulation: The process of apoptosis (programmed cell death) is crucial in maintaining immune homeostasis. Dysregulation of apoptosis can lead to the survival of autoreactive lymphocytes, contributing to autoimmunity. Research has shown that cytokines can influence apoptosis-related factors and death receptors, further implicating apoptosis in the pathogenesis of autoimmune diseases [55].

  5. Metabolic Reprogramming: Emerging evidence suggests that metabolic changes within immune cells are significant in the development of autoimmune diseases. These metabolic alterations can affect the activation and function of T and B cells, promoting inflammatory responses [50].

  6. Epigenetic Modifications: Epigenetic changes, such as DNA methylation and histone modifications, can disrupt immune tolerance and contribute to the pathogenesis of autoimmune diseases. These modifications can affect gene expression related to immune responses and are increasingly recognized as important in understanding autoimmunity [4].

In terms of therapies targeting these immune mechanisms, there is a shift from traditional non-specific immunosuppressants towards more targeted approaches. Current and emerging therapies include:

  • Biological Therapies: These include monoclonal antibodies that target specific cytokines (e.g., TNF-α inhibitors) or immune cells (e.g., B-cell depleting agents). These therapies have demonstrated efficacy in managing diseases like rheumatoid arthritis and lupus [54].

  • Antigen-Specific Immunotherapies: Recent advancements have focused on developing therapies that specifically target autoreactive T and B cells, aiming to restore immune tolerance without broadly suppressing the immune system [51].

  • Nanovaccines: Innovative approaches using nanotechnology are being explored to induce immune tolerance by delivering antigens in a way that modifies the immune response without eliciting a strong inflammatory reaction [53].

  • Cytokine Therapies: Targeting cytokine signaling pathways is a promising strategy to correct immune dysregulation in autoimmune diseases [19].

Overall, understanding the multifaceted mechanisms underlying autoimmune diseases has paved the way for the development of novel therapeutic strategies that aim to provide more precise and effective treatments, addressing the unmet medical needs in this area.

5.3 Future Directions in Autoimmune Therapy ​

Autoimmune diseases are characterized by the immune system's aberrant response against the body's own tissues, leading to chronic inflammation, tissue damage, and systemic dysfunction. The mechanisms underlying these diseases are multifactorial and include genetic predisposition, environmental triggers, and dysregulated immune responses. Specifically, the pathogenesis involves complex interactions between various components, including T and B cell reactivity, loss of immune tolerance, and epigenetic modifications that contribute to autoreactive lymphocyte activation and tissue destruction [1][51].

Genetic factors play a crucial role in the susceptibility to autoimmune diseases, with certain human leukocyte antigen (HLA) variants being strongly associated with conditions such as rheumatoid arthritis and systemic lupus erythematosus. Environmental factors, including infections and exposure to certain chemicals, can trigger the onset of these diseases in genetically predisposed individuals [1]. The disruption of immunological tolerance mechanisms, which normally prevent the activation of self-reactive lymphocytes, is central to the development of autoimmunity [19].

Current therapeutic strategies for managing autoimmune diseases primarily involve non-specific immunomodulators that may lead to broad immunosuppression, resulting in significant adverse effects. These treatments often fail to address the underlying dysregulation of the immune system. Therefore, there is an urgent need for precise, target-specific therapies that can effectively modulate the immune response without compromising overall immunity [51][56].

Recent advances in the understanding of immune tolerance mechanisms have paved the way for the development of antigen-specific immunotherapies. These strategies aim to restore immune tolerance by specifically targeting the pathogenic immune responses while sparing normal immune function. Techniques such as CAR T-cell therapy, bispecific antibodies, and next-generation immune checkpoint modulators are being explored as innovative approaches to treat autoimmune disorders [57].

Looking to the future, the integration of nanomaterials and mRNA vaccine technologies holds promise for inducing antigen-specific immune tolerance, which could revolutionize the treatment landscape for autoimmune diseases. Furthermore, ongoing research into the epigenetic regulation of immune responses may provide insights into new therapeutic avenues that address the underlying causes of autoimmunity [4][19].

In summary, the mechanisms of autoimmune diseases are complex and involve genetic, environmental, and immunological factors. While current therapies are largely symptomatic and non-specific, emerging strategies focusing on antigen-specific approaches and the understanding of immune tolerance offer hope for more effective treatments in the future. Continued research is essential to refine these therapies and enhance their efficacy and safety for patients suffering from autoimmune disorders [1][51][57].

6 Challenges and Future Perspectives ​

6.1 Gaps in Current Research ​

Autoimmune diseases are characterized by a dysregulated immune response where the immune system mistakenly attacks the body's own tissues. The mechanisms underlying these diseases are complex and multifactorial, involving a combination of genetic, environmental, and immunological factors.

One fundamental mechanism of autoimmunity is the defective elimination and/or control of self-reactive lymphocytes. This imbalance between effector and regulatory immune responses typically progresses through stages of initiation and propagation, with phases of clinical remissions and exacerbations. Genetic predisposition, particularly involving variants of human leukocyte antigen (HLA), plays a significant role in determining an individual's susceptibility to autoimmune diseases. In addition, environmental triggers such as infections and chemical exposures have been implicated in the breakdown of immune tolerance, leading to autoimmunity [58].

Recent research highlights the role of somatic mutations as a novel risk factor contributing to autoimmunity. These mutations can lead to the persistent proliferation of self-reactive lymphocytes by allowing them to bypass regulatory checkpoints, which typically prevent autoimmunity [59]. Furthermore, epigenetic modifications, such as alterations in DNA methylation and histone modifications, have been shown to affect gene expression and immune responses, potentially perpetuating autoreactive responses [4].

Theories regarding environmental influences on autoimmunity suggest that various factors, including infections and exposure to environmental toxins, can disrupt immune tolerance through mechanisms such as molecular mimicry, epitope spreading, and the activation of innate immune responses [7]. For instance, the association between Epstein-Barr virus (EBV) infection and multiple sclerosis underscores the potential role of infections in triggering autoimmune conditions [60].

Despite significant advancements in understanding the mechanisms of autoimmune diseases, several challenges and gaps remain in current research. The exact triggers for disease onset are still poorly understood, and existing therapeutic interventions primarily modify disease courses rather than providing cures [61]. Additionally, the genetic and environmental contributions to autoimmunity are highly variable among different diseases, complicating the development of universally effective treatment strategies [1].

Future research directions must focus on elucidating the precise molecular pathways involved in the initiation and progression of autoimmune diseases. Integrating findings from genomic, transcriptomic, and epigenomic studies may provide a more comprehensive understanding of the pathogenesis of these disorders. Moreover, the exploration of precision medicine approaches, which tailor therapies based on individual genetic and environmental profiles, holds promise for improving outcomes in patients with autoimmune diseases [16].

In summary, the mechanisms of autoimmune diseases involve a complex interplay of genetic predisposition, environmental factors, and immune dysregulation. Addressing the existing gaps in research and enhancing our understanding of these mechanisms will be crucial for developing more effective therapeutic strategies in the future.

6.2 The Importance of Personalized Medicine ​

Autoimmune diseases arise from a complex interplay of various mechanisms that disrupt the body's ability to distinguish between self and non-self, leading to immune-mediated damage to host tissues. The fundamental underlying mechanism of autoimmunity involves the defective elimination and/or control of self-reactive lymphocytes, which can be attributed to both genetic predispositions and environmental triggers.

A critical aspect of autoimmune disease mechanisms is the breakdown of immunologic tolerance, which can occur due to defects in central tolerance (thymic deletion of autoreactive T cells) and peripheral tolerance mechanisms that normally regulate potentially autoreactive T cells (Bluestone & Bour-Jordan, 2012). Regulatory T cells (Tregs) and other regulatory mechanisms, such as the action of cytokines like IL-10, play a significant role in maintaining this tolerance. When these regulatory mechanisms fail, autoreactive T and B cells can escape elimination, leading to the development of autoimmune responses (Yang et al., 2018).

Environmental factors also significantly contribute to the onset of autoimmune diseases. Factors such as infections, chemicals, and other external stimuli can trigger autoimmune responses through mechanisms like molecular mimicry, where pathogens share structural similarities with self-antigens, thus provoking an immune response against the host's own tissues (Benoist & Mathis, 2001; Selmi et al., 2012). The role of the microbiota and epigenetic changes, such as DNA methylation and histone modifications, has been increasingly recognized as crucial in the initiation and perpetuation of autoimmunity (Ahmadi et al., 2017; Costenbader et al., 2012).

The complexity of autoimmune diseases is further highlighted by the involvement of multiple genetic factors, including specific human leukocyte antigen (HLA) variants, which can influence individual susceptibility to autoimmune conditions (Song et al., 2025). The heterogeneity of these diseases means that different mechanisms may predominate in different individuals or even within the same individual over time.

Challenges in the field of autoimmune research include the need for a deeper understanding of the molecular and cellular pathways involved in autoimmunity, as well as the identification of precise environmental triggers. As the field evolves, there is a growing recognition of the importance of personalized medicine approaches that consider the unique genetic, epigenetic, and environmental contexts of individuals with autoimmune diseases. This perspective aims to tailor interventions based on specific disease mechanisms and patient characteristics, ultimately leading to more effective and targeted therapeutic strategies (Pisetsky, 2023).

In summary, the mechanisms underlying autoimmune diseases are multifaceted, involving a combination of genetic predispositions, environmental triggers, and the failure of regulatory immune mechanisms. Continued research is essential to unravel these complexities and to advance personalized medicine in the treatment of autoimmune disorders.

6.3 Strategies for Improving Patient Outcomes ​

Autoimmune diseases are characterized by the immune system's aberrant response to self-tissues, leading to chronic inflammation and tissue damage. The mechanisms underlying these diseases are complex and multifactorial, involving genetic, epigenetic, environmental, and immunological factors.

A fundamental mechanism of autoimmunity is the defective elimination and/or control of self-reactive lymphocytes. This can occur due to failures in both central tolerance, where autoreactive T and B cells are eliminated during their development, and peripheral tolerance, where regulatory mechanisms that normally suppress these cells are impaired (Rosenblum et al., 2015; Bluestone & Bour-Jordan, 2012). Regulatory T cells (Tregs) and molecules such as CTLA-4 and IL-10 play critical roles in maintaining tolerance by eliminating autoreactive cells that have escaped negative selection (Yang et al., 2018). When these mechanisms fail, it can lead to the activation of autoreactive lymphocytes and the subsequent development of autoimmune diseases.

Genetic predisposition also significantly contributes to the risk of developing autoimmune diseases. Certain genetic variants, particularly those associated with human leukocyte antigen (HLA) genes, have been implicated in susceptibility to these conditions (Song et al., 2025). Moreover, environmental factors, including infections, chemicals, and dietary components, can act as triggers for autoimmunity in genetically susceptible individuals (Selmi et al., 2012). For instance, viral infections have been linked to the onset of various autoimmune diseases, suggesting that molecular mimicry—whereby the immune response to an infection cross-reacts with self-antigens—may play a role in disease pathogenesis (Benoist & Mathis, 2001).

Epigenetic mechanisms, such as DNA methylation and histone modifications, have also been recognized as important factors in the pathogenesis of autoimmune diseases. These modifications can lead to changes in gene expression without altering the underlying DNA sequence, potentially contributing to the loss of immune tolerance and the perpetuation of autoreactive responses (Ahmadi et al., 2017; Araki & Mimura, 2017). The interaction between genetic predisposition and environmental influences through epigenetic changes represents a significant area of ongoing research.

Addressing the challenges associated with autoimmune diseases requires a multifaceted approach. Current therapeutic strategies primarily focus on immunosuppression and managing symptoms; however, they often do not target the underlying causes of the diseases. Emerging therapies, including biologics and small molecules that specifically target pathogenic pathways, offer promise in restoring immune balance and improving patient outcomes (Song et al., 2025). Additionally, advances in precision medicine, which tailor treatments based on individual genetic and environmental profiles, may enhance the effectiveness of interventions.

Future perspectives in the field of autoimmunity will likely focus on understanding the complex interplay between genetic, epigenetic, and environmental factors, as well as the identification of novel biomarkers for early diagnosis and monitoring disease progression. This comprehensive understanding will be essential for developing more effective, targeted therapies that not only alleviate symptoms but also address the root causes of autoimmune diseases, ultimately improving patient outcomes.

7 Conclusion ​

The mechanisms underlying autoimmune diseases are intricate and multifaceted, involving a complex interplay of genetic predisposition, environmental triggers, and dysregulated immune responses. Key findings indicate that genetic factors, particularly specific human leukocyte antigen (HLA) variants, play a significant role in susceptibility to autoimmune conditions. Environmental influences, including infections and exposure to chemicals, can activate autoimmune processes in genetically predisposed individuals. Furthermore, the dysregulation of immune responses, characterized by an imbalance between effector and regulatory lymphocytes, is central to the pathogenesis of these diseases. Emerging research highlights the importance of epigenetic modifications and metabolic reprogramming in influencing immune function and promoting autoimmunity. The therapeutic landscape is evolving from traditional non-specific immunosuppressants towards more targeted approaches, including antigen-specific immunotherapies and microbiome modulation, which hold promise for restoring immune tolerance and improving patient outcomes. Future research should focus on elucidating the precise molecular pathways involved in autoimmunity, integrating genomic and environmental data to inform personalized medicine strategies that cater to individual patient profiles. This approach aims to enhance the effectiveness of interventions and address the unmet needs in managing autoimmune diseases.

References ​

  • [1] Xiaoshuang Song;Hantian Liang;Fang Nan;Wenjing Chen;Junyao Li;Liu He;Yiping Cun;Zhenhong Li;Wei Zhang;Dunfang Zhang. Autoimmune Diseases: Molecular Pathogenesis and Therapeutic Targets.. MedComm(IF=10.7). 2025. PMID:40529617. DOI: 10.1002/mco2.70262.
  • [2] David S Pisetsky. Pathogenesis of autoimmune disease.. Nature reviews. Nephrology(IF=39.8). 2023. PMID:37165096. DOI: 10.1038/s41581-023-00720-1.
  • [3] Shu-Han Yang;Cai-Yue Gao;Liang Li;Christopher Chang;Patrick S C Leung;M Eric Gershwin;Zhe-Xiong Lian. The molecular basis of immune regulation in autoimmunity.. Clinical science (London, England : 1979)(IF=7.7). 2018. PMID:29305419. DOI: 10.1042/CS20171154.
  • [4] Majid Ahmadi;Tohid Gharibi;Sanam Dolati;Davood Rostamzadeh;Saeed Aslani;Behzad Baradaran;Vahid Younesi;Mehdi Yousefi. Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases.. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie(IF=7.5). 2017. PMID:28086135. DOI: 10.1016/j.biopha.2016.12.072.
  • [5] Yasuto Araki;Toshihide Mimura. The Histone Modification Code in the Pathogenesis of Autoimmune Diseases.. Mediators of inflammation(IF=4.2). 2017. PMID:28127155. DOI: 10.1155/2017/2608605.
  • [6] Karen H Costenbader;Steffen Gay;Marta E Alarcón-Riquelme;Luca Iaccarino;Andrea Doria. Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?. Autoimmunity reviews(IF=8.3). 2012. PMID:22041580. DOI: 10.1016/j.autrev.2011.10.022.
  • [7] Carlo Selmi;Patrick S C Leung;David H Sherr;Marilyn Diaz;Jennifer F Nyland;Marc Monestier;Noel R Rose;M Eric Gershwin. Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop.. Journal of autoimmunity(IF=7.0). 2012. PMID:22749494. DOI: .
  • [8] Jean-François Bach. Revisiting the Hygiene Hypothesis in the Context of Autoimmunity.. Frontiers in immunology(IF=5.9). 2020. PMID:33584703. DOI: 10.3389/fimmu.2020.615192.
  • [9] Vered Molina;Yehuda Shoenfeld. Infection, vaccines and other environmental triggers of autoimmunity.. Autoimmunity(IF=3.1). 2005. PMID:16126512. DOI: 10.1080/08916930500050277.
  • [10] Shaye Kivity;Nancy Agmon-Levin;Miri Blank;Yehuda Shoenfeld. Infections and autoimmunity--friends or foes?. Trends in immunology(IF=13.9). 2009. PMID:19643667. DOI: 10.1016/j.it.2009.05.005.
  • [11] Annarosa Floreani;Patrick S C Leung;M Eric Gershwin. Environmental Basis of Autoimmunity.. Clinical reviews in allergy & immunology(IF=11.3). 2016. PMID:25998909. DOI: 10.1007/s12016-015-8493-8.
  • [12] Kenneth Michael Pollard;Dwight H Kono. Requirements for innate immune pathways in environmentally induced autoimmunity.. BMC medicine(IF=8.3). 2013. PMID:23557436. DOI: 10.1186/1741-7015-11-100.
  • [13] K Michael Pollard;Joseph M Christy;David M Cauvi;Dwight H Kono. Environmental Xenobiotic Exposure and Autoimmunity.. Current opinion in toxicology(IF=3.6). 2018. PMID:29503968. DOI: 10.1016/j.cotox.2017.11.009.
  • [14] Haijing Wu;Yongjian Chen;Huan Zhu;Ming Zhao;Qianjin Lu. The Pathogenic Role of Dysregulated Epigenetic Modifications in Autoimmune Diseases.. Frontiers in immunology(IF=5.9). 2019. PMID:31611879. DOI: 10.3389/fimmu.2019.02305.
  • [15] Jingyue Li;Mingjiu Zhao;Wenjun Luo;Jiaqi Huang;Bin Zhao;Zhiguang Zhou. B cell metabolism in autoimmune diseases: signaling pathways and interventions.. Frontiers in immunology(IF=5.9). 2023. PMID:37680644. DOI: 10.3389/fimmu.2023.1232820.
  • [16] Nancy Agmon-Levin;Zhexiong Lian;Yehuda Shoenfeld. Explosion of autoimmune diseases and the mosaic of old and novel factors.. Cellular & molecular immunology(IF=19.8). 2011. PMID:21358666. DOI: 10.1038/cmi.2010.70.
  • [17] Manoj Kumar;Linda Yip;Fangyuan Wang;Saci-Elodie Marty;C Garrison Fathman. Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies?. Frontiers in immunology(IF=5.9). 2025. PMID:40852720. DOI: 10.3389/fimmu.2025.1626082.
  • [18] G H Ring;F G Lakkis. Breakdown of self-tolerance and the pathogenesis of autoimmunity.. Seminars in nephrology(IF=3.5). 1999. PMID:9952278. DOI: .
  • [19] Farzana Yasmeen;Rameez Hassan Pirzada;Bilal Ahmad;Bogeum Choi;Sangdun Choi. Understanding Autoimmunity: Mechanisms, Predisposing Factors, and Cytokine Therapies.. International journal of molecular sciences(IF=4.9). 2024. PMID:39062908. DOI: 10.3390/ijms25147666.
  • [20] Mark A Exley;George C Tsokos;Kingston H G Mills;Dirk Elewaut;Ben Mulhearn. What rheumatologists need to know about innate lymphocytes.. Nature reviews. Rheumatology(IF=32.7). 2016. PMID:27586381. DOI: 10.1038/nrrheum.2016.140.
  • [21] Shuyi Wang;Niansheng Yang;Hui Zhang. Metabolic dysregulation of lymphocytes in autoimmune diseases.. Trends in endocrinology and metabolism: TEM(IF=12.6). 2024. PMID:38355391. DOI: 10.1016/j.tem.2024.01.005.
  • [22] Urs Christen;Matthias G von Herrath. Initiation of autoimmunity.. Current opinion in immunology(IF=5.8). 2004. PMID:15511670. DOI: 10.1016/j.coi.2004.09.002.
  • [23] C Benoist;D Mathis. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?. Nature immunology(IF=27.6). 2001. PMID:11526389. DOI: 10.1038/ni0901-797.
  • [24] A Tincani;L Andreoli;C Bazzani;D Bosisio;S Sozzani. Inflammatory molecules: a target for treatment of systemic autoimmune diseases.. Autoimmunity reviews(IF=8.3). 2007. PMID:17967717. DOI: 10.1016/j.autrev.2007.03.001.
  • [25] Suresh Kumar Karri;A Sheela. Potential route of Th17/Treg cell dynamics in targeting type 1 diabetes and rheumatoid arthritis: an autoimmune disorder perspective.. British journal of biomedical science(IF=4.6). 2017. PMID:28074676. DOI: 10.1080/09674845.2016.1264704.
  • [26] Kalpana Manthiram;Qing Zhou;Ivona Aksentijevich;Daniel L Kastner. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation.. Nature immunology(IF=27.6). 2017. PMID:28722725. DOI: 10.1038/ni.3777.
  • [27] Ludmiła Szewczak;Katarzyna Donskow-Łysoniewska. Cytokines and Transgenic Matrix in Autoimmune Diseases: Similarities and Differences.. Biomedicines(IF=3.9). 2020. PMID:33271810. DOI: 10.3390/biomedicines8120559.
  • [28] M G Cavallo;P Pozzilli;R Thorpe. Cytokines and autoimmunity.. Clinical and experimental immunology(IF=3.8). 1994. PMID:8149655. DOI: 10.1111/j.1365-2249.1994.tb06220.x.
  • [29] Fatima Dandash;Zahraa Salhab;Rawan Issa;Zeinab Al Dirani;Mariam Hamze;Gabriel Fares;Fatima Berro;Fatima Shaalan;Ali Hamade;Makram Merimi;Mehdi Najar;Rayan Dakroub;Douaa Khreis;Mohammad Fayyad-Kazan;Hussein Fayyad-Kazan. Targeting the double-edged sword: cytokines in the pathogenesis and treatment of autoimmune diseases.. Inflammopharmacology(IF=5.3). 2025. PMID:40580299. DOI: 10.1007/s10787-025-01817-8.
  • [30] Anna Donniacuo;Arianna Mauro;Chiara Cardamone;Anna Basile;Paola Manzo;Jelena Dimitrov;Anna Lisa Cammarota;Liberato Marzullo;Massimo Triggiani;Maria Caterina Turco;Margot De Marco;Alessandra Rosati. Comprehensive Profiling of Cytokines and Growth Factors: Pathogenic Roles and Clinical Applications in Autoimmune Diseases.. International journal of molecular sciences(IF=4.9). 2025. PMID:41009491. DOI: 10.3390/ijms26188921.
  • [31] Xinlian He;Pingxian Liu;Youfu Luo;Xinyuan Fu;Tao Yang. STATs, promising targets for the treatment of autoimmune and inflammatory diseases.. European journal of medicinal chemistry(IF=5.9). 2024. PMID:39180944. DOI: 10.1016/j.ejmech.2024.116783.
  • [32] V Paunovic;H P Carroll;K Vandenbroeck;M Gadina. Signalling, inflammation and arthritis: crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity.. Rheumatology (Oxford, England)(IF=4.4). 2008. PMID:18238793. DOI: 10.1093/rheumatology/kem352.
  • [33] Claire Gorby;Jonathan Martinez-Fabregas;Stephan Wilmes;Ignacio Moraga. Mapping Determinants of Cytokine Signaling via Protein Engineering.. Frontiers in immunology(IF=5.9). 2018. PMID:30319612. DOI: 10.3389/fimmu.2018.02143.
  • [34] Xuebin Liu;Lei Fang;Taylor B Guo;Hongkang Mei;Jingwu Z Zhang. Drug targets in the cytokine universe for autoimmune disease.. Trends in immunology(IF=13.9). 2013. PMID:23116550. DOI: .
  • [35] Walaa K Mousa;Fadia Chehadeh;Shannon Husband. Microbial dysbiosis in the gut drives systemic autoimmune diseases.. Frontiers in immunology(IF=5.9). 2022. PMID:36341463. DOI: 10.3389/fimmu.2022.906258.
  • [36] Xiaojing Cui;Yanguang Cong. Role of Gut Microbiota in the Development of Some Autoimmune Diseases.. Journal of inflammation research(IF=4.1). 2025. PMID:40162082. DOI: 10.2147/JIR.S515618.
  • [37] Nahir Garabatos;Pere Santamaria. Gut Microbial Antigenic Mimicry in Autoimmunity.. Frontiers in immunology(IF=5.9). 2022. PMID:35572569. DOI: 10.3389/fimmu.2022.873607.
  • [38] Maran L Sprouse;Nicholas A Bates;Krysta M Felix;Hsin-Jung Joyce Wu. Impact of gut microbiota on gut-distal autoimmunity: a focus on T cells.. Immunology(IF=5.0). 2019. PMID:30560993. DOI: 10.1111/imm.13037.
  • [39] Mathis Wolter;Erica T Grant;Marie Boudaud;Alex Steimle;Gabriel V Pereira;Eric C Martens;Mahesh S Desai. Leveraging diet to engineer the gut microbiome.. Nature reviews. Gastroenterology & hepatology(IF=51.0). 2021. PMID:34580480. DOI: 10.1038/s41575-021-00512-7.
  • [40] Hongli Wang;Yueshu Cai;Wenqi Wu;Miaomiao Zhang;Yong Dai;Qingwen Wang. Exploring the role of gut microbiome in autoimmune diseases: A comprehensive review.. Autoimmunity reviews(IF=8.3). 2024. PMID:39384149. DOI: 10.1016/j.autrev.2024.103654.
  • [41] Kristina Hoffman;Zackariah Brownell;William J Doyle;Javier Ochoa-Repáraz. The immunomodulatory roles of the gut microbiome in autoimmune diseases of the central nervous system: Multiple sclerosis as a model.. Journal of autoimmunity(IF=7.0). 2023. PMID:36435700. DOI: 10.1016/j.jaut.2022.102957.
  • [42] Bo Li;Carlo Selmi;Ruqi Tang;M E Gershwin;Xiong Ma. The microbiome and autoimmunity: a paradigm from the gut-liver axis.. Cellular & molecular immunology(IF=19.8). 2018. PMID:29706647. DOI: 10.1038/cmi.2018.7.
  • [43] Márcia S Pereira;Martin A Kriegel. Evolving concepts of host-pathobiont interactions in autoimmunity.. Current opinion in immunology(IF=5.8). 2023. PMID:36444784. DOI: 10.1016/j.coi.2022.102265.
  • [44] Peilin Zhang;Lawrence M Minardi;J Todd Kuenstner;Steven M Zekan;Rusty Kruzelock. Anti-microbial Antibodies, Host Immunity, and Autoimmune Disease.. Frontiers in medicine(IF=3.0). 2018. PMID:29876352. DOI: 10.3389/fmed.2018.00153.
  • [45] Serena Martinelli;Giulia Nannini;Fabio Cianchi;Francesco Coratti;Amedeo Amedei. The Impact of Microbiota-Immunity-Hormone Interactions on Autoimmune Diseases and Infection.. Biomedicines(IF=3.9). 2024. PMID:38540229. DOI: 10.3390/biomedicines12030616.
  • [46] Thabit Moath Omar;Karar H Alfarttoosi;Gaurav Sanghvi;R Roopashree;Aditya Kashyap;T Krithiga;Waam Mohammed Taher;Mariem Alwan;Mahmood Jasem Jawad;Ali M Ali Al-Nuaimi. Engineering the Microbiome: a Novel Approach to Managing Autoimmune Diseases.. Neuromolecular medicine(IF=3.9). 2025. PMID:40911227. DOI: 10.1007/s12017-025-08879-5.
  • [47] Theresa L Montgomery;Daniel Peipert;Dimitry N Krementsov. Modulation of multiple sclerosis risk and pathogenesis by the gut microbiota: Complex interactions between host genetics, bacterial metabolism, and diet.. Immunological reviews(IF=8.3). 2024. PMID:38717158. DOI: 10.1111/imr.13343.
  • [48] Ruixue Yang;Zhenzhen Chen;Jun Cai. Fecal microbiota transplantation: Emerging applications in autoimmune diseases.. Journal of autoimmunity(IF=7.0). 2023. PMID:37117118. DOI: 10.1016/j.jaut.2023.103038.
  • [49] Artem Vorobyev;Ralf J Ludwig. Research in practice: Diet and microbiome in autoimmune diseases.. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG(IF=3.8). 2023. PMID:37235511. DOI: 10.1111/ddg.15101.
  • [50] Hoim Jeong;Beomgu Lee;Seung Jin Han;Dong Hyun Sohn. Glucose metabolic reprogramming in autoimmune diseases.. Animal cells and systems(IF=3.2). 2023. PMID:37465289. DOI: 10.1080/19768354.2023.2234986.
  • [51] Yi Song;Jian Li;Yuzhang Wu. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders.. Signal transduction and targeted therapy(IF=52.7). 2024. PMID:39362875. DOI: 10.1038/s41392-024-01952-8.
  • [52] Xueting Yu;Yaping Mai;Yaya Wei;Na Yu;Ting Gao;Jianhong Yang. Therapeutic potential of tolerance-based peptide vaccines in autoimmune diseases.. International immunopharmacology(IF=4.7). 2023. PMID:36696858. DOI: 10.1016/j.intimp.2023.109740.
  • [53] Yuhong Tang;Lili Li. The Application of Nanovaccines in Autoimmune Diseases.. International journal of nanomedicine(IF=6.5). 2024. PMID:38229706. DOI: 10.2147/IJN.S440612.
  • [54] Cristina Balagué;Steven L Kunkel;Núria Godessart. Understanding autoimmune disease: new targets for drug discovery.. Drug discovery today(IF=7.5). 2009. PMID:19596080. DOI: 10.1016/j.drudis.2009.07.002.
  • [55] Matilde Todaro;Ann Zeuner;Giorgio Stassi. Role of apoptosis in autoimmunity.. Journal of clinical immunology(IF=5.7). 2004. PMID:14997028. DOI: 10.1023/B:JOCI.0000018057.89066.c6.
  • [56] Jingjing Chen;Xiaoming Wang. Epigenetic regulation of B cell response in autoimmune diseases.. Current opinion in immunology(IF=5.8). 2025. PMID:40451141. DOI: 10.1016/j.coi.2025.102582.
  • [57] May A Alsayb. Innovations in immunotherapy for autoimmune diseases: recent breakthroughs and future directions.. Frontiers in immunology(IF=5.9). 2025. PMID:41041324. DOI: 10.3389/fimmu.2025.1647066.
  • [58] Michael D Rosenblum;Kelly A Remedios;Abul K Abbas. Mechanisms of human autoimmunity.. The Journal of clinical investigation(IF=13.6). 2015. PMID:25893595. DOI: .
  • [59] Maha Alriyami;Constantin Polychronakos. Somatic Mutations and Autoimmunity.. Cells(IF=5.2). 2021. PMID:34440825. DOI: 10.3390/cells10082056.
  • [60] Gunnar Houen. Auto-immuno-deficiency syndromes.. Autoimmunity reviews(IF=8.3). 2024. PMID:39209011. DOI: 10.1016/j.autrev.2024.103610.
  • [61] Mark Plander;Bernadette Kalman. Rare autoimmune disorders with Mendelian inheritance.. Autoimmunity(IF=3.1). 2016. PMID:27207228. DOI: 10.1080/08916934.2016.1183658.

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

autoimmune diseases · genetic factors · environmental triggers · dysregulated immune responses · cytokine signaling

© 2025 MaltSci