Autoimmune Disease and Allergy Notes

Immune Tolerance - An Overview

Innate and Adaptive Immune Tolerance

Immune tolerance includes:

  • Innate tolerance: Trained immunity (as discussed by Prof. Cathy Thornton).
  • Adaptive immune tolerance: Involves T-cells and B-cells.

Adaptive Immune Tolerance

T-cells and B-cells
  • T-cell receptor (TCR): Contains an antigen-binding site with variable regions, a transmembrane region, and constant regions, consisting of an alpha ($\alpha$) and beta ($\beta$) chain.
  • B-cell receptor (Surface immunoglobulin): Contains an antigen-binding site with light and heavy chains, variable regions, transmembrane region and constant regions.

Central and Peripheral Tolerance

Adaptive immune tolerance occurs in:

  • Central Tolerance:
    • Occurs in primary lymphoid organs: Thymus (for T-cells) and Bone Marrow (for B-cells).
    • Involves thymic selection for T-cells.
    • B-cell selection in the bone marrow.
  • Peripheral Tolerance:
    • Occurs in secondary lymphoid organs: Spleen, Lymph nodes (including tonsils, adenoids, bronchus, mesenteric, Peyer's patch).
    • Involves cell reprogramming.

B-Cell Selection

The stages of B-cell selection:

  1. Stem cell
  2. Early pro-B cell
  3. Late pro-B cell
  4. Large pre-B cell
  5. Small pre-B cell
  6. Immature pre-B cell: Expresses IgM.
  7. Mature pre-B cell: Expresses both IgM and IgD.

These stages occur in the bone marrow, where central tolerance is established. Mature B-cells can then differentiate into:

  • Memory B cells
  • Plasma cells (terminally differentiated)
    • These can migrate to the bone marrow (spleen and blood) or lymph-node follicle (secondary lymphoid organ) where peripheral tolerance is active.
    • Plasma cells produce IgA and IgG.

T-Cell Selection

  • Based on positive and negative selection using available thymic self-antigens (approximately 60% effective).
  • Positive selection: Very low binding. If binding is insufficient to survive, the cell is ineffective at detecting viruses.
  • Too much binding leads to apoptosis.

Thymic Antigens

  • Involves factors like Fezf2 and Aire to open the way for 'self' antigens.
  • Fezf2:-dependent 'self.'
    • Classical transcription factor
  • Aire:-dependent 'self.'
    • Co-activator
  • LTBR, RANK/CD40.
  • TRA (Tissue Restricted Antigens)
  • Chromatin opening
  • Release of stalled polymerase
  • Facilitation of mRNA maturation
  • Histone H3.

Peripheral Tolerance of T-cells

Mechanisms include:

  • Ignorance: No binding of TCR.
  • Anergy: Strong binding of TCR with co-inhibitor molecules leading to Activation, but doesn’t mobilize.
    • Can produce cytokines like IL-4 for allergy response.
  • Overactivation because the antigen is too common (e.g., bacterial superantigens).
  • Phenotypic skewing.
  • Apoptosis.
  • Thymic tolerance

Cells Facilitating Peripheral Tolerance

  • Regulatory T-cells.
  • Tolerogenic dendritic cells.
  • Lymph node stromal cells.

Regulatory T-cells (T-Regs)

  • Most described type are Foxp3+.
  • Can be produced in the thymus (nTreg) or periphery (iTreg).
  • Generated in the Thymus from ($CD4^+$ $CD8^-$) cells that express Foxp3
  • Naive T cells can be differentiated into: TReg, Th17, Th1, and Th2
    • T-Regs: require IL-2, RA, -TGF-$\beta$-

TRegs and Cytokine Production

  • Negatively regulate T-cell activation: via T-cell/Dendritic cell interactions.
  • Produce anti-inflammatory cytokines.
  • Important for pregnancy
  • Produce anti-inflammatory cytokines
  • Th1
    • T-bet, Runx3
    • IFN-$\gamma$, IL-2
    • Activated by IL-12
    • Involved in Autoimmune disease and Anti-tumor immunity
  • Th2
    • GATA-3
    • IL-4, 5, 10, 13
    • Activated by IL-4
    • Involved in Parasite infection and Allergy
  • Th17
    • ROR$\gamma$t
    • IL-17
    • Activated by IL-6, TGF-$\beta$
    • Involved in Autoimmune disease and Microbial immunity

Hypersensitivity and Allergy

Loss of Tolerance

Hypersensitivity is a normal but (subjectively) undesirable response of the immune system.

  • Allergy (+ Anaphylactic shock): Response to a foreign antigen that is not pathogenic.
  • Autoimmune disease: Response to a self-antigen that is not cancerous.
  • Combination of allergic and autoimmune diseases (e.g. Coeliac).
  • Transplant rejection.
  • Sepsis.

Types of Hypersensitivity

Gell and Coombes classification (1963) modified to modern understanding:

  • Biased toward adaptive immunity and exclusive of innate-mediated mechanisms (e.g. NETosis).

Type I - IgE-mediated (Traditional Allergy)

  • Involves allergen presentation by dendritic cells to naive T cells.
  • IL4 is needed for B cells to create IgE
  • Th2 cells stimulate B cells to produce IgE.
    • IgE floods in blood from plasma cells.
  • IgE primes mast cells via Fc receptors.
  • Sensitized mast cells degranulate upon antigen encounter releasing vasoactive amines, lipid mediators, cytokines leading to Increased Permeability, Vasodilation, Bronchospasm, and Epithelial Cell injury.

Type II – Antibody-mediated (e.g. IgG, IgM)

  • Targeted killing of cells.
  • Involves T-cells and innate cells (NK cells, monocytes, macrophages, neutrophils).
  • Complement recruitment and stabilisation.

Type III – Immune complex-mediated

  • Involves complexes of antibody with antigen that can be multivalent and form macroscopic protein masses.
  • Results in:
    1. Thrombosis
    2. Neutrophil granule release/NETs
    3. Monocyte cytokine elevation (complement mediated)

Type IV - Delayed T-Cell-mediated

  • Sensitization Phase:
    • Metal ions (e.g., Ni²⁺) or haptens modify proteins.
    • Langerhans cells and dermal DCs process and present antigens.
    • Nickel directly activates TLR4
    • Cytokines (IL-1$\beta$, TNF$\alpha$, TSLP)
  • Elicitation Phase:
    • Mature DCs migrate to draining lymph nodes.
    • Naive T cells differentiate into effector T cells (like an anti-viral response).
    • Effector T cells cause allergic responses in the skin.

Overview of Hypersensitivities

  • Type I: IgE mediated - Th2 response (Mast cell, Eosinophil and Basophil) – Associated with traditional allergic responses (Hay fever).
  • Type II: Antibody mediated.
  • Type III: Immune complex mediated.
  • Type IV: Delayed (CD8+ T-cell mediated)
  • Type V: Modification of cell receptors by antibodies
  • Type ?: NETosis-mediate, complement-mediated, platelet-

Autoimmune Disease

What is Autoimmune Disease?

  • A response to self-antigens - When immune tolerance fails.
  • Can act through all types I-V of hypersensitive immunity.
  • Combined diseases affect around 5% of populations in Western countries.
  • Women disproportionately affected.

Factors Influencing Autoimmune Diseases

  • Can be determined by genetic or environmental factors e.g.
    • Allergens such as Gluten trigger autoimmune disease.
    • Autoimmune diseases are more likely with specific HLA alleles.
    • Inflammation increases the risk of autoimmune disease.

Stages of Autoimmune Disease

  1. Initiation
  2. Pathology
  3. Flares and remissions

Terminology

  • Autoimmunity: when the body is damaged as a result of the immune system
  • Autoimmune disease: when autoimmunity causes disease
  • Normally considered to be a targeted attack against self-antigens causing a specific disease and not generally collateral damage from immune activity (some exceptions – e.g. IBD – killing microbiome)
  • Targeted attack: involves the adaptive immune system (B- and/ or T-cells) creating a specific response
  • Despite genetic risk factors, autoimmunity is almost always Triggered.

Autoimmunity Triggers

  • Microbiome
  • Diet
  • Climate
  • Exposure
  • Hormones
  • Puberty
  • Parturition
  • Infection
  • Allergy
  • Tissue damage
  • Stress
  • Obesity
  • Inflammation
  • Environment
  • Drugs/ topical agents
  • Clothing (washing powder, watches)
  • Allergens
  • Genetics

Autoimmunity Pathology

  • Involves different types of hypersensitivity reactions.
  • Type I (Allergy): Allergen + IgE + FCER + Degranulation.
  • Type II (Antibody-mediated): Cytotoxic cell + Complement activation.
  • Type III (Immune complex-mediated): Immune complex + Tissue damage.
  • Type IV (Delayed type hypersensitivity): Sensitized T cell + Activated macrophage.
  • Type V (+): Surface cell + Cytokines

Autoimmunity Flares and Remission

  • Flares: Are the chronic recurring pathology of autoimmune disease – often has systemic symptoms (e.g. High CRP and IL-6).
  • Remission: Is when the pathology lessens (not gone).

Mechanisms of Autoimmune Disease

Examples of Autoimmune Diseases

  • Coeliac disease: Combined allergy & autoimmune (Type IV – but also II and III).
  • Systemic lupus erythematosus (SLE): Autoimmune (considered to be types II & III).
  • Rheumatoid arthritis: Autoimmune (Broadly types II to V).

Coeliac Disease

  • Combined allergy & autoimmune disease.
  • Antigen can be deaminated gluten (allergy) or tissue transaminase-gluten complex (autoimmune).
  • HLA alleles determine likelihood of disease – gut damage can accelerate development.
  • Mechanism: Gluten peptides are processed and presented by dendritic cells, leading to Th1 and Th2 responses. This leads to tissue damage through activation of CD8+ IELs, NK cells, and the production of anti-tTG/antigliadin antibodies.
    • Increased Cytokines
    • Retrotranscytosis
    • slgA
    • CD8+ IEL
    • Tissue damage

Outcomes

  • Good outcome: Gluten-free diet effectively eliminates disease; small amounts of gluten are tolerated (an allergy to deaminated gluten).
  • Intermediate outcome: Gluten-free diet mostly eliminates disease, but only trace amounts can trigger a flare (allergy/autoimmune).
  • Bad outcomes: Antibodies or responses to tissue transaminase-gluten complex can still have activity on transaminase alone (full autoimmune).

Rheumatoid Arthritis

  • Mixture of different disease pathologies.

  • Generally a Th1 immune response that is treated well with anti-inflammatory drugs (e.g. anti-TNF, anti-JAK, anti-IL6, dexamethasone).

  • Triggered by inflammation in the joint over long use (aging) which results in the release of DAMPs

  • Autoantibodies are produced

  • Citrullination – Conversion of arginine by peptidylarginine deiminases (e.g. PAD2)

  • Anti-citrullinated protein autoantibodies (ACPA) produced

  • Immune complex (Type III) - Immune complexes form between citrullinated protein, ACPA autoantibodies and rheumatoid factor (RF)

  • Antibody Type II – Binds Fc receptors – Cytokine production

  • Antibody Type V – Binds citrullinated receptors (including Vimentin)

Flares and Remission

  • Flare and remission depends on joint use
  • Wrists and ankles are used the most so have the highest degree of damage (minor inflammation)
  • Vicious cycle between use and autoimmune damage
  • Anti-inflammatory drugs can lead to remission, but cannot remove autoantibodies or T- and B-cells associated with their construction

Systemic Lupus Erythematosus (SLE)

  • A systemic disease that can be life threatening - glomerularnephritis
  • Manifests in sites of inflammation or cell turnover
  • Characterised by anti-nuclear antibodies
  • More common in women
  • Involves
    • Type II
    • Type V
    • Type III
  • NETosis

SLE Glomerulonephritis

  • Involves deposition of NET DNA, LL37, and anti-RNP antibodies in the glomerulus, leading to inflammation and tissue damage.

T-Regs in SLE

  • SLE, like many chronic inflammatory disease involves high levels of IL-6

  • IL-6 is a suppressor of T-reg function!

  • This coupled with a low level of IL-2 effectively takes T-regs out of the picture

  • Anti-inflammatory drugs can lead to remission, but cannot remove autoantibodies or T- and B-cells associated with their construction

  • DNA/ Nuclear proteins are deposited regularly so antibodies are retained even in remission

  • Chronic infection or disease can lead to flares

Summary

  • Autoimmune diseases include lupus, rheumatoid arthritis and coeliac disease

  • Autoimmune disease results in a break from self-tolerance and mechanisms for pathology include all types of immune hypersensitivity (Type I-V)

  • Allergy is the response to a foreign antigen that is not pathogenic

  • The tradition allergy response is a type I hypersensitive response: dendritic cell sensing of allergen, presentation to Th2 cells, IL-4 stimulation of B-cells, IgE priming of mast cells, mast cell response to allergen Allergy can also be Type II-IV responses that involve Th1 immune cells e.g. neutrophils

Exam paper

Compulsory further reading:

JCI INSIGHT

RESEARCH ARTICLE

A neutrophil/TGF-$\beta$ axis limits the

pathogenicity of allergen-specific CD4+
T cells

Gregory S. Whitehead, Seddon Y. Thomas, Keiko Nakano, Derek J. Royer, Catherine G. Burke,

Hideki Nakano, and Donald N. Cook

https://insight.jci.org/articles/view/150251

  • Forced switch to Th1 immunity defends from allergy
    • Th2 (Allergy/ Anti-parasite)
      • Fast immune reaction
    • Th0
      • ‘Resting immune system’
    • Th1 (Anti-bacterial/Anti-viral)
      • Fast immune reaction
  • More energy/time
    • Less likely to get allergies – more prone to parasitic infection
    • More prone to a viral or bacterial infection
    • Sick (colds, bacterial infection)
    • Allergy/Parasite infection
  • Slower switch to Th2 – less eosinophils
    • LPS/OVA priming
    • Neutrophil recruitment and functions
    • Less allergy
    • Immune system training