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14 Bioinformatics of Autoimmune Diseases
FIGURE 1.10 Cytokines and chemokines and their receptors.
1.2.4 MAJOR HISTOCOMPATIBILITY COMPLEX
The MHC (see Figure 1.11) is a gene cluster encoding surface proteins essential for antigen pre-
sentation and immune recognition. Located on chromosome 6 in humans, where it is known as the
HLA system, MHC enables T lymphocytes to distinguish self from non-self and is among the most
polymorphic regions of the genome, promoting population-level immunity to diverse pathogens
(Trowsdale & Knight, 2013).
MHC molecules are classied into class I and class II based on structure, distribution, and function. Class I MHC is expressed on nearly all nucleated cells and presents peptides (8–10 amino acids)
derived from intracellular proteins. These peptides are processed by the proteasome, transported
into the endoplasmic reticulum (ER) via transporter associated with antigen processing (TAP), and
loaded onto MHC class I molecules, composed of a polymorphic α chain and β2-microglobulin.
The peptide–MHC complex is then displayed on the cell surface for recognition by CD8+ cytotoxic
T cells, enabling the elimination of infected or malignant cells (Neefjes etal., 2011).
Class II MHC is expressed primarily on professional APCs, including DCs, macrophages, and
B cells. It presents peptides (13–25 amino acids) from extracellular proteins internalized through
phagocytosis or endocytosis. MHC class II molecules assemble in the ER with an invariant chain (Ii)
that blocks premature peptide binding. After trafcking to endosomal compartments, Ii is degraded
and peptide loading is facilitated by HLA-DM. The resulting complex is transported to the cell
surface for recognition by CD4+ helper T cells, initiating adaptive immune responses (Roche &
Furuta, 2015).
MHC polymorphism underlies individual variability in immune responsiveness. Each person
inherits a unique set of MHC alleles, which shapes the peptide repertoire presented to T cells. While
advantageous for pathogen defense, this diversity presents a major obstacle in organ transplantation
due to immune rejection of mismatched MHC molecules.
MHC also plays a key role in T-cell education. In the thymus, developing T cells undergo positive
selection for weak self-MHC recognition and negative selection against strong self-reactivity. This
dual process ensures immune competence while minimizing the risk of autoimmunity.
FIGURE 1.11 Structural comparison of MHC class I and MHC class II molecules.
15 Immune Mechanisms and Major Autoimmune Diseases
1.2.5 IMMUNOGENIC SELF-PROTEINS
Self-proteins can become immunogenic through structural modications, aberrant expression, or
altered immunological context, bypassing tolerance mechanisms and initiating autoimmunity (see
Figure 1.12). A major trigger is post-translational modication (PTM), where enzymatic changes
such as citrullination, phosphorylation, or oxidation generate neo-epitopes. In rheumatoid arthritis
FIGURE 1.12 This schematic diagram illustrates the major molecular and cellular mechanisms by which
self-proteins can become immunogenic and trigger autoimmune responses.
16 Bioinformatics of Autoimmune Diseases
(RA), peptidylarginine deiminase (PAD) enzymes convert arginine to citrulline in proteins like
brinogen and vimentin, leading to the production of anti-citrullinated protein antibodies (ACPAs),
a disease hallmark (Schellekens etal., 1998). In SLE, oxidative modications and defective clearance
of apoptotic or NETotic debris expose nuclear antigens, which can trigger chronic inammation and
anti-nuclear antibody production (Knight etal., 2012). Neutrophil extracellular traps (NETs) (web-
like chromatin structures released by neutrophils) are especially implicated when dysregulated.
Molecular mimicry is another pathway, where structural similarities between microbial and selfantigens lead to cross-reactive immune responses. These responses may be sustained by PTMs or
structural changes from tissue damage (Oldstone, 2005). Protein misfolding and aggregation can
also unmask cryptic epitopes. In T1D, ER stress in pancreatic β cells alters insulin processing, producing peptides that activate autoreactive CD4+ T cells (Wan etal., 2005). Epigenetic dysregulation
and ectopic antigen expression also contribute. In APECED, AIRE gene mutations impair thymic
expression of self-antigens, resulting in survival of autoreactive T cells that later attack peripheral
tissues (Anderson & Su, 2016).
Overall, self-proteins become immunogenic not solely due to intrinsic features but through a
combination of biochemical alteration, mislocalization, and context, often triggered by infection,
stress, or genetic predisposition.
1.3 COMMON AUTOIMMUNE DISORDERS
Autoimmune diseases comprise a diverse and growing group of disorders, with over 80 identied
to date and additional variants continuing to emerge as research advances. These conditions can
affect nearly every organ system (including skin, joints, nervous tissue, and internal organs) and
often present with overlapping and heterogeneous symptoms. Collectively, they impact an estimated
5–10% of the global population, with a notable female predominance and rising incidence in recent
decades.
Given their variability in clinical features and pathogenesis, each autoimmune disease must be
understood in its own context, as diagnostic criteria, disease course, and treatment options can differ widely. The sections that follow examine the most prevalent autoimmune disorders, highlighting
their causes, target tissues, diagnostic approaches, and therapeutic strategies.
1.3.1 RHEUMATOID ARTHRITIS
RA is a chronic autoimmune disease affecting approximately 0.5–1% of the global population,
with a higher incidence in women between the ages of 30 and 60 (Firestein & McInnes, 2017). It
is marked by persistent synovial inammation, symmetric polyarthritis, joint damage, and systemic manifestations. Without timely intervention, RA can lead to progressive disability and organ
involvement.
The disease arises from complex interactions between genetic susceptibility, environmental
triggers, and immune dysregulation. The strongest genetic association involves HLA-DRB1 alleles
encoding the “shared epitope”, which facilitates autoreactive T-cell activation (Gregersen etal.,
1987). Environmental exposures, particularly cigarette smoking, contribute by inducing citrullina-
tion of self-proteins, leading to the formation of ACPAs, a key serologic marker for RA.
Immunopathology centers on synovial inltration by macrophages, T and B cells, and DCs.
These cells drive synovial hyperplasia, pannus formation, and destruction of cartilage and bone.
Fibroblast-like synoviocytes (FLS) adopt a pathogenic phenotype, producing matrix metalloproteinases and pro-inammatory cytokines. The resulting joint destruction is mediated by both cellmediated responses and immune complexes.
RA is systemic in nature, with extra-articular manifestations, including interstitial lung disease,
cardiovascular complications, and ocular inammation. Chronic inammation accelerates atherosclerosis and contributes to premature mortality (Firestein & McInnes, 2017).
17 Immune Mechanisms and Major Autoimmune Diseases
FIGURE 1.13 This owchart illustrates the sequential events leading to the development of rheumatoid
arthritis activation.
Figure 1.13 illustrates the pathogenic cascade, highlighting how genetic risk and environmental
factors converge to break immune tolerance and initiate chronic synovial inammation.
Tables 1.4 and 1.5 list key genes associated with RA and their functional impact, distinguish-
ing between established and emerging genetic risk loci, respectively. Established loci reect wellcharacterized immune mechanisms central to disease pathogenesis, while emerging loci highlight
novel regulatory pathways and offer insight into potential therapeutic targets (Okada etal., 2014).
Diagnosis is based on clinical presentation, serologic markers (ACPAs, rheumatoid factor (RF)),
and imaging (X-ray, magnetic resonance imaging (MRI), ultrasound). Morning stiffness, joint
swelling, and erosive changes are typical features. Anti-CCP positivity correlates with more severe
disease and structural damage.
Treatment aims for remission or low disease activity. First-line therapy involves methotrexate,
often in combination with other conventional synthetic DMARDs. Patients unresponsive to these
agents may receive biologic DMARDs (e.g., TNF inhibitors, IL-6 receptor blockers, B cell depletion)
18 Bioinformatics of Autoimmune Diseases
TABLE 1.4
Key Established Genetic Risk Loci in Rheumatoid Arthritis
Gene/Locus Chromosome Impact/Role
HLA-DRB1 6p21 Presents citrullinated antigens to T cells, driving RA.
PTPN22 1p13.2 Disrupts TCR signaling and promotes self-tolerance loss.
STAT4 2q32.2 Promotes Th1/Th17 differentiation, linked to severe RA.
TRAF1-C5 9q33-q34 Modulates TNF and complement pathways, inammation.
PADI4 1p36.13 Promotes citrullination and ACPA-generating autoantigens.
TNFAIP3 (A20) 6q23
CTLA4 2q33 Suppresses T cells; dysfunction raises autoimmunity risk.
Inhibits NF-κB; variants promote chronic inammation.
TABLE 1.5
Key Emerging Genetic Risk Loci in Rheumatoid Arthritis
Gene/Locus Chromosome Impact/Role
CCR6 6q27 Directs Th17 migration to joints; associated with ACPA+ RA.
IL2RA (CD25) 10p15.1 Regulates Tregs; variants disrupt immune tolerance.
BLK 8p23-p22 Regulates B-cell signaling; variants linked to autoantibodies.
PRKCQ 10p15 T-cell activation; variants promote pathogenic T-cell survival.
FCGR2A/FCGR3A 1q23 Regulate Fc receptor signaling; immune complex clearance.
CD40 20q13.12 Promotes B cell; amplies antibody-mediated inammation.
TYK2 19p13.2 Emerging JAK–STAT gene; involved in cytokine signaling.
ANKRD55 5q11.2 Regulates pro-inammatory cytokines; under study.
or targeted synthetic DMARDs such as JAK inhibitors (tofacitinib, baricitinib) (Smolen etal., 2018).
Disease activity is monitored using indices such as DAS28, CDAI, or SDAI. Immunosuppressive
therapies require close safety monitoring, including regular lab assessments and updated vaccinations. Ongoing challenges include treatment resistance, disease heterogeneity, and lack of predictive
biomarkers. Emerging research explores novel targets like BTK and GM-CSF, as well as the role of
the gut microbiome in RA pathogenesis.
In summary, RA is a multifactorial autoimmune disease driven by immune intolerance to modied self-antigens. Early recognition and tailored therapy are critical to preventing irreversible joint
damage and improving patient outcomes.
1.3.2 SYSTEMIC LUPUS ERYTHEMATOSUS
SLE is a chronic autoimmune disease marked by widespread inammation and the production of
autoantibodies against nuclear antigens. It affects primarily women of reproductive age and presents
with highly variable clinical features. Hallmark autoantibodies include anti-dsDNA, anti-Sm, antiRo (SSA), and anti-La (SSB), which form immune complexes that drive tissue inammation and
organ damage (Tsokos, 2011).
SLE arises from a convergence of genetic, hormonal, environmental, and immunological factors.
Key susceptibility genes include HLA-DRB1, IRF5, STAT4, PTPN22, and TREX1, which modulate
antigen presentation, B-cell function, and interferon signaling (Harley etal., 2008). Overactivation
of the type I interferon pathway is a dening immunological feature, promoting autoreactive T and
B cell survival and expansion.
19 Immune Mechanisms and Major Autoimmune Diseases
FIGURE 1.14 This owchart illustrates the sequential events leading to the development of the systemic
lupus erythematosus.
Epigenetic mechanisms, such as DNA hypomethylation in T cells and dysregulated microRNA
(miRNA) expression, contribute to immune activation. Environmental triggers (including UV radiation, Epstein–Barr virus (EBV), and smoking) promote apoptotic cell death, oxidative stress, and
exposure of nuclear autoantigens, initiating or exacerbating disease.
Estrogen also inuences disease expression by enhancing B cell responses and shifting the
immune balance toward autoantibody production. This may account for the strong female predominance observed in SLE.
Figure 1.14 illustrates the immunopathogenic process. Defective clearance of apoptotic cells
allows nuclear antigens to persist and be recognized by TLR7 and TLR9 on DCs and B cells, stimulating type I interferon production. This cascade activates autoreactive CD4+ T cells and plasma
cells, which produce a broad array of pathogenic autoantibodies. Immune complexes formed with
these autoantibodies deposit in tissues, triggering inammation and complement activation.
Chronic immune complex deposition affects multiple organs (including the kidneys, skin, joints,
and vasculature) leading to symptoms such as rash, arthritis, nephritis, and vasculitis. Cytokines
such as IFN-α, TNF-α, and IL-6 sustain inammation and tissue damage.
Table 1.6 summarizes key genetic loci associated with SLE, including HLA and non-HLA genes,
which inuence B cell signaling, immune complex clearance, and inammatory regulation (Harley
etal., 2008; Tsokos, 2011).
SLE manifests across a broad clinical spectrum. Common signs include malar rash, photosensitivity, oral ulcers, serositis, arthritis, hematologic abnormalities, and renal or neuropsychiatric
involvement. Lupus nephritis, a major complication in ~50% of patients, is classied histologically
and often requires immunosuppressive therapy.
Diagnosis is based on combined clinical and serological criteria. Positive antinuclear antibody
(ANA) is highly sensitive, while anti-dsDNA and anti-Sm are more specic. Disease activity and
organ involvement guide both diagnosis and treatment decisions.
Management focuses on controlling ares, preserving organ function, and minimizing long-term
damage. Hydroxychloroquine remains the cornerstone of therapy. Corticosteroids manage acute
ares, while immunosuppressants such as azathioprine, mycophenolate, and cyclophosphamide are
used for moderate to severe disease.
20 Bioinformatics of Autoimmune Diseases
TABLE 1.6
Key Genes and Loci Implicated in SLE
Gene/Locus Chromosome Function/Impact
HLA-DRB11501/0301 6p21.3 MHC class II alleles are strongly linked to SLE susceptibility in Caucasians.
IRF5 7q32 TF in the type I IFN pathway; risk alleles elevate immune activation.
STAT4 2q32.2-q32.3 TF activated by IL-12/IL-23; variants linked to increased SLE risk.
PTPN22 1p13.2 Tyrosine phosphatase regulates TCR signaling; linked to autoimmunity.
TREX1 3p21.31 DNA exonuclease; mutations cause DNA buildup and trigger autoimmunity.
BLK 8p23.1 B lymphoid tyrosine kinase; variants alter BCR signaling; autoantibodies.
BANK1 4q24 B-cell scaffold protein with ankyrin repeats; variants affect B-cell activation.
TNFAIP3 6q23.3
ITGAM 16p11.2 Mediates leukocyte adhesion and migration; risk alleles linked to SLE.
FCGR2B 1q23.3 Low-afnity IgG Fc receptor; SNPs impact immune complex clearance.
DNASE1L3 3p14.3 Degrades DNA; mutations impair apoptotic DNA clearance.
PDCD1 2q37.3 PD-1: Variants may impair immune tolerance.
Encodes A20, a negative NF-κB regulator; variants prolong inammation.
Biologic agents have expanded therapeutic options. Belimumab targets BAFF to reduce B cell
survival and are frequency. Anifrolumab, an IFN-α receptor antagonist, offers additional benet in active SLE. Rituximab is used in refractory cases, particularly with renal or hematologic
involvement.
Despite progress, SLE remains a complex and unpredictable disease. Long-term outcomes
depend on early diagnosis, individualized therapy, and continuous monitoring. Research into
genetic risk, epigenetic regulation, and precision medicine continues to inform the development of
more effective and targeted treatments.
1.3.3 TYPE 1 DIABETES MELLITUS
T1D Mellitus is a chronic autoimmune disease characterized by the selective destruction of pancreatic β cells, resulting in absolute insulin deciency and lifelong dependence on exogenous insulin
(Atkinson etal., 2014). Unlike type 2 diabetes, T1D is driven by immune-mediated loss of tolerance
rather than insulin resistance. Though T1D can develop at any age, onset most often occurs during
childhood or adolescence. Rising incidence, especially in industrialized nations, suggests environmental factors may interact with genetic susceptibility to promote disease (Knip etal., 2005).
Figure 1.15 illustrates the pathogenic sequence. The strongest genetic risk is conferred by HLA
class II alleles (HLA-DR and HLA-DQ), which inuence antigen presentation and T-cell selection.
However, environmental triggers (such as viral infections, altered microbiota, early infant feeding, and seasonal factors) likely initiate or accelerate disease in genetically predisposed individuals
(Rewers & Ludvigsson, 2016).
Beta cell antigens including insulin, GAD65, IA-2, and ZnT8 are presented in an inammatory
context, triggering autoreactive CD4+ and CD8+ T cells. Cytotoxic T cells inltrate islets and mediate β cell destruction, while autoreactive B cells produce islet-specic autoantibodies, often detectable before clinical onset. Cytokines such as IFN-γ, I L-1β, and TNF-α amplify local inammation
and apoptosis. Persistent β cell loss results in hyperglycemia and the classic symptoms of diabetes.
Without management, patients are at risk for long-term complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathy.
Table 1.7 summarizes major genetic risk loci. In addition to HLA-DRB1/DQA1/DQB1, other
important loci include INS (affecting thymic insulin expression), PTPN22 (T-cell signaling),
CTLA4 (immune regulation), IL2RA (Treg function), and IFIH1 (viral sensing). These loci reect
21 Immune Mechanisms and Major Autoimmune Diseases
FIGURE 1.15 This owchart illustrates the sequential events leading to the development of type 1 diabetes.
the intersection of autoimmunity, central tolerance, and host–pathogen interactions (Firestein &
McInnes, 2017).
Standard treatment relies on lifelong insulin replacement via injections or pumps. Advances such
as continuous glucose monitoring (CGM) and closed-loop systems have improved glycemic control
but do not modify the autoimmune basis of disease.
Recent research has focused on immune-based and regenerative approaches. Teplizumab, an
anti-CD3 monoclonal antibody, delays T1D onset by modulating autoreactive T cells (Herold etal.,
2019). Antigen-specic tolerance strategies (such as insulin or GAD65 DNA vaccines) aim to restore
immune regulation without broad immunosuppression (Ludvigsson, 2016).
In parallel, stem cell-derived β-like cells offer a promising source for β cell replacement. These
cells can be protected from immune attack using encapsulation technologies that allow insulin
secretion while blocking immune access (Pagliuca etal., 2014). Though early in clinical develop-
ment, these therapies signal a shift toward disease-modifying interventions.
TABLE 1.7
Major Genetic Loci Implicated in Type 1 Diabetes Mellitus
Gene/Locus Chromosome Function Impact on T1DM Risk
HLA class II 6p21 Antigen presentation to Accounts for ~50% of genetic risk; DR3-DQ2
(HLA-DRB1, Tcells and DR4-DQ8 alleles markedly increase
DQA1, DQB1) susceptibility.
INS (insulin gene) 11p15 Insulin production VNTR SNPs modulate thymic insulin levels
and immune tolerance.
PTPN22 1p13 T-cell receptor signaling R620W variant associated with increased
regulation autoimmunity risk.
CTLA4 2q33 Negative regulation of T-cell Variants linked to impaired immune regulation
activation and higher autoimmunity risk.
IL2RA (CD25) 10p15 Regulatory T-cell function Variants affect IL-2 signaling, impacting
immune tolerance.
IFIH1 2q24 Viral RNA recognition Variants may alter antiviral responses,
inuencing autoimmunity.
22 Bioinformatics of Autoimmune Diseases
1.3.4 MULTIPLE SCLEROSIS
MS is a chronic autoimmune disease of the central nervous system (CNS), characterized by inammation, demyelination, and progressive neurodegeneration. The immune system aberrantly targets
the myelin sheath, disrupting signal conduction and leading to neurological dysfunction. As demyelination progresses, sclerotic plaques form in the brain, spinal cord, and optic nerves, often accompanied by axonal injury (Reich etal., 2018).
MS arises from the interaction of genetic and environmental factors. The strongest genetic risk
is associated with HLA-DRB1*15:01, a class II allele involved in antigen presentation. Genomewide association studies (GWAS) have identied over 200 additional loci that inuence immune
regulation, including genes involved in T-cell signaling, cytokine responses, and antigen processing
(International Multiple Sclerosis Genetics Consortium, 2019). Among environmental triggers, EBV
infection is strongly associated with MS, along with vitamin D deciency and smoking, all of which
contribute to immune dysregulation and increased susceptibility (Bjornevik etal., 2022).
Figure 1.16 outlines MS pathogenesis: genetic susceptibility primes the immune system, while
environmental factors such as EBV infection or low vitamin D levels trigger activation of autoreactive Th1 and Th17 CD4+ T cells. These cells cross the blood–brain barrier, recognize CNS antigens
(e.g., myelin basic protein), and initiate inammation. B cells contribute by producing intrathecal
antibodies and supporting chronic inammation, leading to oligodendrocyte loss, demyelination,
and axonal damage.
Table 1.8 lists key genetic loci associated with MS. HLA-DRB1*15:01 remains the principal risk
allele, while non-HLA genes further implicate immune regulation in disease development (De Jager
etal., 2009).
Clinically, MS presents in distinct forms. The most common is relapsing-remitting MS (RRMS),
marked by episodes of neurological symptoms followed by recovery. Over time, many patients
transition to secondary progressive MS (SPMS). Less frequent forms include primary progressive
MS (PPMS), characterized by steady worsening, and progressive-relapsing MS, now considered
a PPMS variant (Lublin et al., 2014). Diagnosis is based on the McDonald criteria, requiring
CNS lesions disseminated in time and space. MRI is central to diagnosis, revealing lesions in
periventricular, juxtacortical, and spinal regions. CSF analysis typically shows oligoclonal IgG
bands. Evoked potentials aid in detecting subclinical demyelination. Treatment aims to reduce
relapse frequency and delay disability progression. First-line therapies include interferon-beta
FIGURE 1.16 This owchart illustrates the sequential events leading to the development of MS.
23 Immune Mechanisms and Major Autoimmune Diseases
TABLE 1.8
Key Genetic Loci Associated with Multiple Sclerosis
Gene Chromosome Functional Role/Impact
HLA-DRB1*15:01 6p21.3 (MHC region) Strongest genetic risk; mediates antigen presentation to CD4+ T cells.
IL2RA (CD25) 10p15.1 Regulates T-cell proliferation; associated with immune tolerance.
IL7R 5p13.2 Critical for T-cell development and survival; associated with MS
susceptibility.
TNFRSF1A 12p13.31 Mediates inammatory responses; variants linked to MS risk.
CD58 1p13.1 Involved in T-cell activation; some alleles protect against MS.
CLEC16A 16p13.13 Involved in autophagy and antigen processing; linked to MS and
autoimmunity.
STAT3 17q21.2 Transcription factor; variants linked to MS risk via cytokine signaling.
IRF8 16q24.1 Regulates immune cell differentiation; associated with MS risk.
TYK2 19p13.2 Involved in cytokine signaling pathways; variants linked to MS susceptibility.
C20orf202 20p13 Function not well characterized; identied as a novel MS susceptibility locus.
and glatiramer acetate. More potent agents include natalizumab (blocks leukocyte CNS entry),
ocrelizumab (B cell depletion), and ngolimod (inhibits lymphocyte migration). Other oral therapies include dimethyl fumarate and teriunomide, which modulate immune responses (Hauser &
Cree, 2020).
While these therapies reduce disease activity, they do not repair damage. Research efforts focus
on neuroprotection and remyelination, using strategies such as stem cell therapy, oligodendrocyte
regeneration, and mitochondrial support. Biomarkers like neurolament light chain (NfL) are
emerging as tools to monitor disease progression and treatment efcacy.
In summary, MS is a heterogeneous autoimmune disease driven by immune-mediated CNS
damage. Advances in genetics, imaging, and immunotherapy continue to improve diagnosis, personalize treatment, and enhance long-term outcomes.
1.3.5 CELIAC DISEASE
Celiac disease is a chronic autoimmune enteropathy triggered by ingestion of gluten (found in wheat,
barley, and rye) in genetically susceptible individuals. It affects about 1% of the global population,
though many cases go undiagnosed due to varied and sometimes silent presentations (Lebwohl
etal., 2018). The condition is tightly associated with HLA-DQ2 and HLA-DQ8 haplotypes, particu-
larly HLA-DQ2.5. However, these alleles are not sufcient for disease onset, as they are present in
~30–40% of the general population without symptoms (Sollid & Jabri, 2013).
The immune response begins when gluten-derived gliadin peptides are deamidated by tissue
transglutaminase (tTG), enhancing their afnity for HLA-DQ2/DQ8 molecules on APCs. This presentation activates gluten-specic CD4+ T cells, leading to cytokine secretion (e.g., IFN-γ, IL-15)
and recruitment of intraepithelial lymphocytes (IELs), which induce enterocyte damage. The result
is villous atrophy, crypt hyperplasia, and mononuclear inltration in the lamina propria (Abadie
etal., 2011).
Figure 1.17 depicts this cascade, from gluten ingestion to mucosal destruction. In genetically
predisposed individuals, gliadin peptides cross the gut barrier (enhanced by zonulin) and are presented by HLA-DQ2/DQ8 on APCs. This activates T helper cells and stimulates B cell production
of anti-tTG and anti-endomysial antibodies, while IELs mediate epithelial injury.
Table 1.9 summarizes major genetic risk loci. HLA-DQA1 and HLA-DQB1 (on 6p21.3) encode
the key molecules DQ2.5 and DQ8. Additional non-HLA genes—IL2/IL21, SH2B3, PTPN2,
TAGAP, CCR2, and TGM2—modulate immune signaling and contribute to pathogenesis.
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