(4.8) AUTOIMMUNITY

Immunology BMS 545 Study Notes

• Course date: December 2, 2024
• Semester topics:
  • Autoimmune disorders (12/2)
  • Case study ("What's Wrong with Me?") (12/4)
  • Immunology debrief: The Well Patient (12/6)
  • Study Day (in-person): 3-5 pm, 12/9
  • Office hours (virtual): 12/10
  • Immunology Exam: 1 pm, 12/11
• Announcements:
  • Office hours:
    • Tuesdays, 4-5 pm (virtual)
    • Thursdays, 4-5 pm (in-person)
  • No more DITKI (review papers, grades posted by end of week)

Prevalence of Autoimmune Diseases

• 23 million Americans have autoimmune diseases
• 18 million are women
• 5 million are men
• Prevalence varies by condition (e.g., Autoimmune thyroiditis: 2,619 per 10^5; Psoriasis/Psoriatic Arthritis: 939 per 10^5)

Objectives for BMS 545 Immunology

• Define autoimmune disorders
• Understand three ways autoimmunity occurs
• Define neoantigens and their consequences
• Identify hypersensitivities mimicking autoimmunity
• Explain body's mechanisms to prevent autoimmunity
• Discuss the need for small amounts of autoimmunity
• Analyze impact of genetics, environmental factors, and gender on autoimmunity
• Identify genes linked to autoimmune diseases and specific diseases
• Understand characteristics of autoimmune diseases in detail, including signs, symptoms, and treatments.

Frankenstein's Monster Case Study

• Hoarse and coarse voice
• Fatigueable ptosis
• Shuffling, difficult gait and severely waxing and waning energy and physical capability
• Information needed:
  • Creation of monster
  • Cause of symptoms
  • Monster's condition

Big Picture: Immune System Tolerance

• B and T cells are selected for survival if they recognize, but do not react to self.
• B cells do not need to recognize self (T cells typically activate them)
• Self-antigens are recognized by T cells
• B cells modifying their receptors.
• B cells becoming anergic upon recognizing monovalent self antigens.
• Immune cells ignore proteins and antigens located in immune-privileged sites (e.g., testes, uterus, eye, brain)

Self-Tolerance

• Immune system failure to respond aggressively to an epitope.
• Central tolerance: inactivation or destruction of lymphocytes during development (in bone marrow & thymus)
• Peripheral tolerance: control or elimination of autoreactive B & T cells after exiting the bone marrow or thymus.
  • Anergy: non-responsiveness in lymphocytes
  • Suppression: regulatory cells inhibiting the activity of other cells

Anergy in T&B Cells

• T-cell activation requires TCR binding to appropriate MHC and secondary signals from APCs.
• Lack of secondary signals leads to T-cell inactivity (anergy).
• Naive CD8+ T-cells can become active if their secondary signals are present.
• Naive B cells can become anergic if their surface immunoglobulins bind to monovalent self-antigens.

Suppression

• Tolerance to self-epitopes may be induced by regulatory T-cells (Tregs)
• Autoimmune responses are linked to a balance between Th1 and Th2 responses.
• Th2 responses to self-epitopes sometimes result in minimal pathology, while Th1 responses can cause detrimental inflammatory responses like delayed-type hypersensitivity (DTH).
• Intestinal epithelial cells produce anti-inflammatory Th2 cytokines (IL-4, IL-10, & TGF-β)
• These cytokines create an environment promoting IgA production and inhibiting inflammatory cell responses.

Loss of Suppression

• Suppressor cells decline with age, increasing the risk of previously suppressed autoreactive lymphocytes becoming active
• Autoimmune disease risk is linked to aging and changes/increases in aging individuals.

What Is Autoimmunity?

• Loss of self-tolerance
• Autoimmune damage: inflammation & immune response from an autoreactive immune response triggering clinically and pathologically manifested anomalies.

Autoimmune Diseases

• Affect various molecules, cells, and tissues
• Result of damage inflicted on cells and tissues due to humoral, cell-mediated, or both immune responses
• Systemic or diffuse due to target antigen distribution (e.g., SLE and rheumatoid arthritis affecting various joints and body tissue)

How Does Autoimmunity Occur?

• Autoimmune induction needs exogenous stimuli and inherent abnormalities.
• Physical trauma exposes the body's immune system to normally sequestered self-antigens.
• Molecular mimicry: antigens resembling self-proteins causing cross-reactivity and pathogenicity.
• Constant exogenous stimuli lead to sustained pro-inflammatory signaling and lack of anti-inflammatory signaling.
• Immune systems become "stuck" in this mode, leading to self-reactive B and T-cell lineages and out-of-control autoimmunity.

Genetics of Autoimmunity

• No single gene is essential for autoimmune diseases
• HLA haplotypes are the strongest genetic associations linked to autoimmune disorders.
• Monozygotic twins show higher consistency for autoimmune diseases compared to dizygotic twins.
• Genetically normal self-HLAs can be modified to initiate auto-reactivity via exogenous or endogenous mutations.

Environmental Triggers of Autoimmunity

• Trauma can cause inflammation & release of sequestered antigens.
• Molecular mimicry: antigenic protein mimicking self-proteins causing auto-reactivity & cross-reactivity.
• Superantigen stimulation can cause cell activation and expansion via MHC-II/TCR complex leading to responses against auto-reactive T cells.

Trauma: Sequestered Antigens

• Self-molecules that are normally "sequestered" within an environment aren't usually exposed to the immune system.
• Exposure can lead to the immune system recognizing them as foreign.
• Examples include developing sperm within testicular tubules, as these are sealed off early and usually do not encounter immune cells.
• Immunoprivileged sites: areas of the body exhibiting some degree of isolation from the immune system (e.g., testes, cornea, anterior eye chamber, brain, uterus during pregnancy).

Sequestered Antigens and the Blood-Brain Barrier

• Composed of tightly packed endothelial cells that restrict cell and large molecule flow into the brain.
• Prevents immune system infiltration, therefore protecting the brain from potentially harmful inflammatory responses.

Cryptic Epitopes

• Molecules may have "immunologically privileged sites" with epitopes (3D configurations) sheltered from the immune system.
• Denaturation or cleavage exposes "hidden" internal epitopes for antibody recognition.
• Rheumatoid factor (RF): an example of a cryptic epitope related to inflammatory rheumatoid diseases.

Molecular Mimicry

• Microbial proteins can resemble self-proteins resulting in cross-reactivity.
• Autoimmune responses are linked to elevated inflammatory cytokines (often produced following activation of phagocytes).
• Elevated cytokines might suffice for activating T cells even without direct APC interaction.
• Autoimmune diseases often develop after an infection.

Association of Cardiac Damage & Rheumatic Fever

• Rheumatic fever often follows Group A strep throat infection
• High levels of antibodies against bacterial M protein (cross-react with cardiac molecules) lead to antibody-induced injury of heart valves and sarcolemma.
• Testing for strep and antibiotic treatment are necessary to reduce antibody responses.

Differential Diagnosis

• Neoantigens: "new" antigens that aren't self-antigens but can trigger conditions mimicking autoimmunity.
• Responses to neoantigens are resolved if the source is removed, while responses to true self-antigens become permanent.
• Molecular mimicry might explain autoimmune tendencies during severe infections like SARS-CoV-2, although this generally resolves once the exogenous antigen is gone.
• Neoantigens in cancer are linked to genetic mutations, viruses, etc., where they stimulate T-cell responses to the cancer cells.

Biological Sex & Autoimmunity

• Autoimmune diseases are more prevalent in women.
• Of 19 common autoimmune diseases, 14 are more common in females.
• Estrogen and prolactin enhance adaptive immune responses.
• Testosterone decreases inflammatory cytokines and enhances Th2 cell lines.

Humoral-Associated Autoimmune Diseases

• Some autoimmune diseases are due to self-reactive antibodies (usually IgG or sometimes IgM), leading to Type II and III hypersensitivity reactions.
• Examples:
  • Myasthenia gravis (Type II)
  • Hashimoto Thyroiditis (Type II)
  • Systemic Lupus Erythematosus (SLE)/Lupus (Type II and III)
  • Rheumatoid arthritis (Type III)

NMJ: Myasthenia Gravis (MG)

• Neuromuscular junction disorder characterized by skeletal muscle weakness and fatigability.
• Etiology: decreased acetylcholine receptors (AChRs).
• Associated with thymoma, thymic hyperplasia, HLA-B8, and certain medications.
• Autoantibodies targeting NMJ protein.
• Symptoms include fluctuating muscle weakness, fatigable chewing, ptosis, diplopia, and dysphagia/dysarthria.

Hashimoto's Thyroiditis

• Antibodies that attack thyroid tissue, and eventually destroy the thyroid gland leading to hypothyroidism.
• Diagnosis often involves analysis of antibodies to thyroid peroxidase (TPO) and other anti-thyroid antibodies and also thyroid-stimulating hormone (TSH).
• Tx is typically thyroid hormone replacement.
• 4- to 10x more common in women.

SLE: Sometimes It’s Really Lupus

• Relapsing, remitting multisystem autoimmune disease that's ANA-positive.
• Primarily associated with Type II and Type III hypersensitivities.
• Butterfly/malar rash on young females, symptoms flaring on sunlight-exposed areas.
• Important markers: Anti-nuclear antibody (ANA).
• Type I: cytotoxic
• Type III: antigen-antibody complex trapping
• Type II: antibodies bind to host cell.

RA: Rheumatoid Arthritis

• HLA-DR4 associated.
• Symmetrical, polyarticular arthritis with proximal migration and joint erosion.
• Anti-citrullinated protein antibody (ACPA), rheumatoid factor (RF), & C-reactive protein (CRP) are key markers.
• Significant extra-articular manifestations.
• More frequent in females.

Cell-Mediated Autoimmune Disease

• Type IV hypersensitivity.
• May include cytotoxic T-cell responses or macrophages and DTH responses.
• Inflammation can become widespread.
• Examples:
  • Type I diabetes (β-cell destruction in pancreas)
  • Multiple sclerosis (CNS demyelination)
• Often involves the loss of tolerance to previously sequestered antigens.

Type 1 Diabetes Mellitus (T1DM)

• HLA-DR3 or DR4
• T-cell-mediated destruction of islet cells in the pancreas leading to autoimmune damage.
• Symptoms include polydipsia, polyuria, polyphagia, weight loss, and diabetic ketoacidosis.
• Elevated HbA1c (blood glucose) and associated complications.
• Associated with numerous downstream consequences.

Multiple Sclerosis (MS)

• HLA-DRB1
• Myelin and oligodendrocyte damage spares PNS.
• Myelin-binding proteins are targets for auto-antibodies.
• Leading neurologic disability in young adults, especially women.
• Episodes and progressive multifocal CNS signs/symptoms.
• Epstein-Barr virus is a potential contributing factor.

Epstein-Barr Virus (EBV) and MS

• A longitudinal analysis of military recruits suggests a high association between EBV infection and increased MS risk.

Autoimmune Progression

• Damage & inflammation sustain progression & amplification of autoimmune pathology through multiple phases.
• Loss of self-tolerance spreads damage.
• Aberrant B & T cell function without negative control leads to autoimmunity and disease progression.

Epitope Spreading

• Response to an epitope leads to autoimmune response involving other self-antigens (epitopes
• Initial reaction to an pathogen may result in self-antigens being exposed.
• This can cause later development of auto-immune responses to different epitopes (self antigens) related to the initial triggering antigen.

Treatment of Autoimmunity

• Super simple: Downregulating inflammation and the immune system.
• Glucocorticoids, monoclonal antibodies, and NSAIDs

Current Research & Rates

• Research is constantly evolving, so rates should be considered in a context of understanding how those rates vary and are impacted by several factors (age, gender, ethnicity).

Test your knowledge on autoimmune disorders, focusing on Myasthenia Gravis, Hashimoto's Thyroiditis, Systemic Lupus Erythematosus, and Rheumatoid Arthritis. This quiz evaluates your understanding of their characteristics, symptoms, and diagnostic criteria.