Role of Susceptibility Genes

Slide 1 · Role of Susceptibility Genes

Genetic architecture of autoimmune susceptibility

HLA associations · Immune regulation · Host–microbe defense

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why common autoimmune diseases are generally multigenic rather than single-gene disorders.

Interpret HLA association data without confusing susceptibility with disease causation.

Connect non-HLA risk loci to lymphocyte signaling, self-tolerance, and microbial sensing.

Distinguish common susceptibility variants from rare single-gene immune dysregulation.

Integrate genetic background with environmental triggers in pathogenesis.

Slide 3 · Autoimmune disease requires more than an allele

Inherited susceptibility

HLA and non-HLA variants

Immune regulation

Central and peripheral tolerance

Environmental context

Infection, inflammation or tissue injury

Pathologic expression

Self-reactive lymphocyte activation and tissue injury

The contributors interact; Inherited variation does not cause environmental exposure.

Slide 4 · Most autoimmune disorders have complex genetic architecture

Inherited susceptibility usually reflects multiple genetic loci acting together.

Risk alleles may be present in healthy individuals; Clinical expression is not inevitable.

Risk loci involve antigen presentation, lymphocyte control, and host responses to microbes.

Common polygenic disease must be distinguished from rare monogenic immune dysregulation.

Slide 5 · Twin studies support a genetic contribution

Evidence from twin studies

Affected individuals’ twins have higher autoimmune disease incidence than the general population.

Concordance is greater in monozygotic than dizygotic twins.

Shared inherited factors therefore contribute to susceptibility.

Limits of that evidence

Twin concordance is not perfect.

Non-genetic influences also matter.

Concordance supports heritability—not a specific causal gene.

The direction of the twin findings here, not an exact concordance percentage.

Slide 6 · Genetic association is not genetic destiny

A susceptibility allele increases disease odds; It does not establish that disease will occur.

The HLA-B27 example is especially instructive: Most carriers never develop ankylosing spondylitis.

Slide 7 · Sources of genetic evidence

Twins and families

Heritable contribution to a phenotype

HLA associations

Alleles associated with immune-mediated disease

Genome-wide association

Common non-MHC susceptibility polymorphisms

Rare human mutations

Loss of individual regulatory pathways

Knockout mouse models

Experimental tests of immune control

Mechanistic studies

Potential pathway connecting variant and disease

An association, a mechanism, and a monogenic disease are different kinds of evidence.

Slide 8 · How loss of self-tolerance produces autoimmunity

Self-reactive lymphocyte

Autoreactivity can arise during receptor generation

Control failure

Deletion, anergy, suppression, or apoptosis is inadequate

Activation

Stimulus permits self-directed effector response

Tissue injury

Antibody and/or T-cell-mediated damage

Risk genes can alter control points in this chain; Environmental stimuli can provide the activating context.

Slide 9 · Central and peripheral tolerance target different stages

Central tolerance

Thymus for developing T cells; Bone marrow for developing B cells.

Deletion of strongly autoreactive clones.

B-cell receptor editing; Thymic regulatory T-cell development.

Peripheral tolerance

Acts on mature lymphocytes after central selection.

Anergy and inhibitory receptor signaling.

Regulatory T-cell suppression and activation-induced apoptosis.

These are parent mechanisms required to understand why some susceptibility genes matter.

Slide 10 · AIRE connects gene expression with central tolerance

Thymic AIRE

Expression of peripheral tissue antigens

Self-antigen display

Developing T cells encounter self

Negative selection

Autoreactive T-cell clones eliminated

Loss-of-function AIRE mutations impair central tolerance and can cause autoimmune polyendocrine disease.

Slide 11 · CTLA-4 restrains peripheral T-cell activation

APC costimulation

B7 costimulator displayed

CTLA-4 activity

Regulatory T cells remove B7 from APCs

Reduced stimulation

Self-reactive T-cell activation restrained

CTLA4 is both a disease-associated susceptibility gene and a rare monogenic checkpoint defect.

Slide 12 · PD-1 provides another inhibitory signal

PD-1 receptor

On responding T cells

Ligand engagement

PD-L1 / PD-L2 bind PD-1

Inhibitory signaling

T-cell activation limited

PD-1 deficiency as mechanistic evidence that immune inhibitory pathways prevent systemic inflammation.

Slide 13 · IL-2 and CD25 sustain regulatory T-cell control

IL-2

T-cell growth and survival signal

CD25 / IL-2Rα

Receptor component on regulatory T cells

Treg maintenance

Suppression of self-reactive responses

IL2RA polymorphisms may change the balance of regulatory and effector T-cell activity.

Slide 14 · Fas–FasL signaling deletes activated autoreactive cells

Self-antigen recognition

Mature T-cell activation

Fas binds FasL

Death receptor pathway engaged

Apoptosis

Potentially self-reactive cells removed

Disruption of FAS or FASL can lead to autoimmune lymphoproliferative syndrome (ALPS).

Slide 15 · Three categories of genetic involvement

HLA / MHC alleles

Variation in the antigen-presenting context

Non-HLA common variants

Variation in immune regulation and microbial defense

Rare single-gene disorders

Direct failure of a defined tolerance checkpoint

The first two account for much of common polygenic risk; The third demonstrates causal pathways.

Slide 16 · HLA genes are major autoimmune susceptibility loci

HLA associations are among the strongest genetic associations in autoimmune disease.

Class I and class II alleles are associated with different disease phenotypes.

Variation in peptide presentation is a plausible mechanism for several associations.

The strength of an association differs across loci, diseases, and populations.

Slide 17 · HLA class I and class II: Distinct contexts

Class I association

HLA-B27 is the striking example in ankylosing spondylitis.

Class I HLA associates with a major increase in disease odds.

The allele is not sufficient to produce disease.

Class II association

Multiple autoimmune diseases show class II HLA associations.

HLA-DR and HLA-DQ alleles feature in the Robbins table.

Certain molecules may preferentially present self or modified-self peptides.

Do not infer that all HLA associations act through the same proved molecular mechanism.

Slide 18 · Antigen presentation links HLA with T-cell recognition

Self-peptide context

Natural or modified self peptide

HLA molecule displays peptide

Autoreactive T cell may respond

Disease context

Relevant HLA allele inherited

Tolerance / regulation is inadequate

Inflammatory activation occurs

Schematic causal possibilities; Individual allele–disease mechanisms vary in certainty.

Slide 19 · The proposed HLA mechanism: Selective peptide display

An HLA molecule binds and displays a subset of available peptides.

Disease-associated alleles may preferentially present natural or modified self peptides.

Certain such associations have mechanistic support, including in rheumatoid arthritis.

Preferential peptide presentation is a disease-specific hypothesis—not a universal proof.

Slide 20 · Association, mechanism, and causation are not synonyms

What an HLA association shows

An allele occurs more frequently among people with a disease.

The estimated odds differ between carrier and noncarrier groups.

It supports inherited susceptibility.

What it does not establish

That every carrier will develop disease.

That the precise biologic pathway is known.

That the allele is sufficient or always required.

Risk alleles modify probabilities; Do not equate them with diagnostic criteria.

Slide 21 · HLA-B27: An exceptional association

Ankylosing spondylitis is associated with HLA-B27 at an approximate odds ratio of 100–200.

This source estimate comes from populations of European ancestry and does not provide absolute risk.

Slide 22 · How to read an odds ratio without overclaiming

OR = 1

No association on the odds scale

OR > 1

Higher disease odds in allele carriers

Absolute risk

Requires the underlying disease frequency

A large odds ratio is not the proportion of carriers who will develop disease.

Slide 23 · Clinical reasoning: HLA-B27 carrier

A healthy adult is incidentally found to carry HLA-B27. They have no history or findings suggestive of ankylosing spondylitis.

Reasoning prompt

What does the carrier result establish about susceptibility?

Can the allele alone establish ankylosing spondylitis?

Why is a 100–200 odds ratio compatible with many healthy carriers?

Slide 24 · Why most HLA-B27 carriers remain unaffected

Carrying HLA-B27 is neither equivalent to having disease nor sufficient for disease development.

Other inherited factors and environmental/immune contexts modify expression.

The high odds ratio expresses a relative association, not a personal prognosis.

A disease diagnosis requires evidence beyond a susceptibility genotype.

Slide 25 · Rheumatoid arthritis: HLA-DRB1 shared epitope

The associated susceptibility alleles share a DRB1 sequence motif at positions 70–74.

Robbins Table 6.7 reports associations specifically for anti-CCP–positive rheumatoid arthritis.

Slide 26 · Shared-epitope alleles in rheumatoid arthritis

One shared-epitope allele

Table 6.7: Approximate odds ratio 4.

DRB1 shared-epitope region: Amino acid positions 70–74.

Estimate applies to anti-CCP–positive rheumatoid arthritis.

Two shared-epitope alleles

Table 6.7: Approximate odds ratio 12.

A stronger genotype association is shown.

These are not direct estimates of penetrance.

Anti-CCP denotes antibodies to cyclic citrullinated peptides.

Slide 27 · HLA associations in anti-CCP–positive rheumatoid arthritis

Disease / phenotype

HLA genotype or haplotype

Approx. OR

RA, anti-CCP positive

DRB1: One shared-epitope allele

4

RA, anti-CCP positive

DRB1: Two shared-epitope alleles

12

Approximate odds ratios reported Table 6.7; European-derived populations.

Slide 28 · Modified-self peptides can connect genotype to autoimmunity

Self protein

Posttranslational modification may occur

Peptide presentation

Some HLA molecules preferentially bind modified self

T-cell activation

Autoimmune response can be promoted

This pathway is an explanatory possibility highlighted for rheumatoid arthritis; It is not inferred from an OR alone.

Slide 29 · Type 1 diabetes: Class II HLA haplotypes

Disease / phenotype

HLA genotype or haplotype

Approx. OR

Type 1 diabetes

DRB1*0301–DQA1*0501–DQB1*0201

4

Type 1 diabetes

DRB1*0401–DQA1*0301–DQB1*0302

8

Type 1 diabetes

DRB1*0301/0401 heterozygotes

35

Distinct haplotype/genotype categories as reported; Not an individual absolute-risk calculator.

Slide 30 · The type 1 diabetes example is genotype dependent

Multiple HLA-DR/DQ haplotypes are associated with increased disease odds.

The table lists a different association for the DRB1*0301/0401 heterozygous genotype.

Genotype combinations cannot be reduced to the effect of one isolated allele.

This does not mean that HLA genotyping alone diagnoses type 1 diabetes.

Slide 31 · HLA associations: Multiple sclerosis and SLE

Disease / phenotype

HLA genotype or haplotype

Approx. OR

Multiple sclerosis

DRB1*1501

3

Systemic lupus erythematosus

DRB1*0301

2

Systemic lupus erythematosus

DRB1*1501

1.3

Approximate odds ratios; Small differences in the table should not be overinterpreted.

Slide 32 · Celiac disease: HLA-DQ association

Disease / phenotype

HLA genotype or haplotype

Approx. OR

Celiac disease

DQA1*0501–DQB1*0201 haplotype

7

Presence of the susceptibility haplotype does not itself establish celiac disease.

Slide 33 · Selected HLA–disease associations at a glance

Disease

Associated HLA category

Approx. OR

Ankylosing spondylitis

HLA-B27

100–200

Anti-CCP+ rheumatoid arthritis

DRB1: One / two shared epitopes

4 / 12

Type 1 diabetes

Listed DR/DQ combinations

4 / 8 / 35

Multiple sclerosis

DRB1*1501

3

Systemic lupus erythematosus

DRB1*0301 / *1501

2 / 1.3

Celiac disease

DQA1*0501–DQB1*0201

7

Source: Robbins Table 6.7; The odds ratios are approximate and population-specific.

Slide 34 · Interpreting Table 6.7: Four essential cautions

The reported odds ratios are approximate, not universal constants.

Table values are drawn from European-derived populations.

Association strength differs by phenotype definition; Rheumatoid arthritis is anti-CCP positive in the table.

An odds ratio cannot be translated to absolute risk without baseline disease probability.

Slide 35 · HLA allele vs haplotype vs genotype

Allele or motif

HLA-B27 denotes a class I allele family.

A DRB1 shared-epitope susceptibility motif spans positions 70–74.

Alleles specify sequence-level variation.

Haplotype or combination

Certain DRB1–DQA1–DQB1 combinations are tabulated for type 1 diabetes.

DRB1*0301/0401 heterozygotes form a distinct category.

Do not apply an OR from one genetic category to another.

Slide 36 · Common non-HLA polymorphisms modify disease susceptibility

Family studies and genome-wide association studies reveal many non-MHC loci.

Some loci are disease-associated; Others recur across multiple autoimmune disorders.

The encoded proteins often regulate lymphocyte responses, tolerance, or microbial defense.

A statistical association does not independently resolve variant function or causal direction.

Slide 37 · From association signal to candidate mechanism

GWAS / family association

Risk-associated locus identified

Molecular localization

Coding or gene-regulatory region

Pathway hypothesis

Protein abundance or immune activity altered

Disease susceptibility

A change in probability, not certainty

The source emphasizes that many implicated polymorphisms lie in regulatory DNA.

Slide 38 · Noncoding regulatory variants vs coding variants

Regulatory polymorphism

Often located in promoters or enhancers.

May change the abundance, timing, or cellular location of gene expression.

Most non-MHC associations discussed are of this broad type.

Protein-coding variant

May change the sequence or function of an encoded protein.

A plausible altered protein function still requires evidence.

The source does not assign a molecular mechanism to every individual allele.

The regulatory-versus-coding distinction is a source-grounded generalization, not a claim about every locus.

Slide 39 · The main non-HLA pathways in the source

Lymphocyte signaling

PTPN22

Regulatory T-cell maintenance

IL2RA / CD25; CTLA4

Th17 differentiation

IL23R

Microbial detection

NOD2

Autophagy / barrier integrity

ATG16L1

Type I interferon responses

IRF5 and IFIH1

These are selected examples Table 6.8, not a comprehensive genetic atlas.

Slide 40 · PTPN22 encodes a protein tyrosine phosphatase

The proposed function involves restraining lymphocyte tyrosine-kinase signaling.

Disease-associated variants are postulated to permit excessive lymphocyte activation.

Slide 41 · PTPN22: A proposed route to lymphocyte hyperactivation

PTPN22 variant

Reduced negative control, as hypothesized

Tyrosine kinases

More prolonged or excessive signaling

Lymphocytes

Increased activation potential

Robbins frames the mechanism as a postulate, not an experimentally settled mechanism for every allele.

Slide 42 · PTPN22 has pleiotropic autoimmune associations

Associations include rheumatoid arthritis and type 1 diabetes.

Table 6.8 additionally includes inflammatory bowel disease.

The same risk locus appears in phenotypically different disorders.

This supports the concept of shared immune regulatory pathways.

Slide 43 · IL2RA variants may alter the effector–Treg balance

IL2RA / CD25

IL-2 receptor α-chain

Changed IL-2 responses

Expression or signaling may differ

Immune balance

Effector and regulatory T cells affected

Reported associations include type 1 diabetes and multiple sclerosis.

Slide 44 · CD25 in disease association and immune tolerance

Normal biologic role

CD25 is part of the IL-2 receptor.

IL-2 is required to maintain functional regulatory T cells.

Regulatory T cells restrain autoreactive lymphocytes.

Disease hypothesis

IL2RA regulatory variants may alter receptor expression.

A changed effector–regulatory balance can modify susceptibility.

Specific consequences depend on the variant and context.

Slide 45 · CTLA4: Common variation and rare defects

Common association

CTLA4 variants are associated with type 1 diabetes and RA

Normal checkpoint

CTLA-4 restrains B7-mediated costimulation

Rare deficiency

Loss of checkpoint can cause systemic immune dysregulation

Independent lines of evidence support this pathway; Common alleles are not equivalent to knockouts.

Slide 46 · IL23R connects susceptibility with Th17 differentiation

IL23R

Receptor for IL-23

CD4 T-cell program

Influences pathogenic Th17 effector differentiation

Inflammatory disease

Associations with IBD, psoriasis and AS

Robbins Table 6.8 proposes an effect on Th17 differentiation; Allele-specific functional changes are not detailed.

Slide 47 · NOD2 senses microbes in the intestinal setting

NOD2 belongs to the intracellular NLR family of microbial sensors.

It is expressed in intestinal epithelial cells, including Paneth cells, and other cells.

NOD2 variants associate with Crohn disease, especially in some ethnic populations.

This illustrates that susceptibility loci can affect barrier–microbe interactions.

Slide 48 · NOD2: Proposed defect in commensal sensing

NOD2 risk variant

Impaired gut microbial recognition (hypothesis)

Barrier–microbe interface

Entry of commensals may increase

Inflammatory response

Persistent response to ordinarily tolerated microbes

The proposed chain is not established for every NOD2-associated patient; Crohn disease is not simply a classic organ-specific autoantibody disorder.

Slide 49 · ATG16L1 links autophagy to intestinal defense

ATG16L1

Autophagy-related gene

Potential functions

Microbial defense and epithelial barrier maintenance

Inflammation

Association with inflammatory bowel disease

The textbook table states a possible role; It does not establish a universal mechanism.

Slide 50 · IRF5 and IFIH1 link susceptibility to type I interferon

IRF5 / IFIH1

Immune sensing and transcriptional pathways

Type I interferon

Associated with cytokine response

SLE susceptibility

Type I interferon is involved in lupus pathogenesis

A source-derived putative pathway; Gene-specific causal alleles are not specified in Table 6.8.

Slide 51 · Non-HLA risk loci: Immune regulation

Gene

Associated diseases

Putative biologic role

PTPN22

RA; T1D; IBD

Lymphocyte signaling / negative control

IL23R

IBD; Psoriasis; AS

IL-23 signaling; Th17 differentiation

CTLA4

T1D; RA

T-cell inhibition / regulatory T-cell effects

IL2RA

MS; T1D

IL-2 signaling; Treg and effector balance

Associations and putative functions are derived Table 6.8.

Slide 52 · Non-HLA risk loci: Response to microbes

Gene

Associated diseases

Proposed function

NOD2

IBD

Cytoplasmic bacterial sensor in gut epithelium

ATG16L1

IBD

Autophagy, microbial defense and epithelial barrier

IRF5; IFIH1

SLE

Type I interferon production / regulation

Inflammatory bowel disease encompasses more than conventional adaptive autoimmunity.

Slide 53 · Two broad classes of non-HLA susceptibility loci

Immune response / tolerance

PTPN22: Lymphocyte kinase signaling.

CTLA4 and IL2RA: Inhibition and Treg homeostasis.

IL23R: Effector T-cell differentiation.

Host–microbe / innate pathways

NOD2: Intracellular microbial recognition.

ATG16L1: Autophagy and intestinal barrier function.

IRF5 and IFIH1: Type I interferon response.

Biological category is not an exclusive cell-type classification.

Slide 54 · Rare single-gene disorders explain immune checkpoints

Knockout experiments and inherited human mutations reveal specific tolerance pathways.

AIRE, CTLA4, PD1, FAS, FASL, IL2, and CD25 among these checkpoints.

Such mutations can produce severe immune dysregulation.

They do not explain most common multigenic autoimmune diseases.

Slide 55 · AIRE deficiency and polyendocrine autoimmunity

Normal AIRE-dependent step

Expression of tissue-restricted self antigens within thymic selection.

Self-reactive developing T cells can encounter those antigens.

Negative selection removes some dangerous clones.

AIRE loss of function

Reduced central display of some self antigens.

Impaired elimination of relevant autoreactive T cells.

Rare autoimmune polyendocrine syndrome may result.

Slide 56 · FOXP3 deficiency illustrates regulatory T-cell failure

FOXP3

Required for functional regulatory T cells

Defective Treg function

Reduced suppression of self-reactive immunity

IPEX

Severe X-linked immune dysregulation

IPEX is an adjacent tolerance example, not a common risk polymorphism listed in Table 6.8.

Slide 57 · FAS / FASL mutations impair lymphocyte deletion

Fas / FasL pathway

Activation-related death signal

Reduced apoptosis

Autoreactive lymphocytes persist

ALPS phenotype

Autoimmune lymphoproliferative syndrome

A direct rare-pathway example rather than a common autoimmune susceptibility allele.

Slide 58 · B-cell IgG Fc receptor supplies negative feedback

Immune complex

IgG bound to antigen

B-cell Fc receptor

Feedback inhibits further antibody production

Receptor knockout

Autoimmunity may develop in experimental models

This pathway is cited in the subsection as experimental evidence of B-cell immune regulation.

Slide 59 · Common susceptibility variants are not null mutations

Polygenic susceptibility

Modest-to-large statistical associations are possible.

Most carriers do not necessarily express disease.

Often noncoding regulatory variants across many loci.

Rare monogenic dysregulation

Defined genetic lesion can disrupt a critical immune pathway.

Provides unusually direct evidence of checkpoint function.

Not responsible for most common autoimmune conditions.

A common association is not evidence of a complete protein knockout.

Slide 60 · Distinct genetic pathways in autoimmune susceptibility

Antigen presentation

HLA class I and class II

Central tolerance

AIRE-dependent thymic selection

Peripheral inhibition

CTLA4, PD-1 and Fas pathways

Effector signaling

PTPN22 and IL23R

Regulatory T cells

IL2RA / CD25 and FOXP3

Innate / barrier defense

NOD2, ATG16L1, IRF5 and IFIH1

These are parallel and interacting mechanisms, not a linear gene-to-gene signaling chain.

Slide 61 · Case: Anti-CCP–positive rheumatoid arthritis

Two people with anti-CCP–positive rheumatoid arthritis have different DRB1 shared-epitope allele counts. The textbook table reports odds ratios of approximately 4 and 12 for the corresponding categories.

Reasoning prompt

What type of association is being compared?

Does the difference show that one patient must have more severe disease?

Can these values alone predict the course of established arthritis?

Slide 62 · Case: Crohn disease and NOD2 susceptibility

A study reports enrichment of a NOD2 polymorphism among people with Crohn disease in a particular ancestry group.

Reasoning prompt

Which innate immune function is implicated by Robbins?

What proposed mechanism might connect microbial recognition to intestinal inflammation?

Which conclusions would require direct functional or clinical data?

Slide 63 · Case: IL2RA association across diseases

An IL2RA regulatory-region polymorphism is associated with type 1 diabetes and multiple sclerosis in genetic studies.

Reasoning prompt

What protein does IL2RA encode?

Which cell population may be especially sensitive to disturbed IL-2 signaling?

Why does a shared locus not imply identical disease pathogenesis?

Slide 64 · Genetic finding: What can be concluded?

HLA-B27 detected

Increased susceptibility to AS; Not a diagnosis

PTPN22 association

A plausible immune-regulatory locus

Rare AIRE loss of function

Can disrupt thymic central tolerance

IL2RA promoter variant

Potential altered IL-2 responsiveness

NOD2 risk polymorphism

Crohn association with contextual mechanism

FAS disruption

Loss of an apoptotic tolerance pathway

Genotype interpretation must match the strength and type of source evidence.

Slide 65 · Five interpretation pitfalls to avoid

Confusing odds ratios with an individual’s probability of disease.

Applying population-specific association estimates to all ancestry groups.

Assuming that HLA carriage is sufficient for a clinical diagnosis.

Treating postulated non-HLA mechanisms as established for every variant.

Using rare knockout phenotypes as models of the magnitude of common-variant effects.

Slide 66 · Susceptibility is expressed through gene–environment interplay

Inherited background

HLA and immune-regulatory variants

Environmental stimuli

Infection, tissue injury and inflammation

Tolerance control

Autoreactive lymphocytes may be restrained or activated

Disease expression

Only a subset of susceptible people develop tissue injury

Risk genes and exposures interact; Neither factor is an isolated sufficient cause.

Slide 67 · Synthesis: What susceptibility genes teach us

HLA associations highlight the importance of antigen presentation.

Non-HLA polymorphisms identify immune regulatory, effector, and innate pathways.

Rare monogenic disorders demonstrate why defined tolerance checkpoints matter.

Disease expression remains probabilistic and depends on additional biologic context.

Slide 68 · Core terminology for accurate genetic interpretation

Term

Meaning in this lecture

Susceptibility allele

Inherited variant associated with altered disease odds

Haplotype

Combination of linked alleles considered together

Shared epitope

Susceptibility-associated motif in HLA-DRB1 positions 70–74

GWAS

Genome-wide association study of genotype–phenotype patterns

Regulatory polymorphism

Variation potentially affecting gene expression

Monogenic immune defect

Rare mutation directly impairing a defined tolerance pathway

Definitions are intended for interpreting the Robbins evidence, not for genetic counseling.

Slide 69 · Primary reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition · Elsevier · 2026.