Autoimmunity

Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. These conditions are more commonly seen in women. Autoimmune diseases are chronic, with clinical manifestations consistent with the associated immune response. Among these conditions are Graves’ disease (autoantibodies against thyroid hormone receptors), myasthenia gravis (antibodies against acetylcholine receptors), type 1 diabetes (pancreatic β-cell destruction by immune cells), and systemic lupus erythematosus (multiorgan damage driven by immune complexes and autoantibodies).

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Overview

Definition

Autoimmunity is the pathologic immune response to self, or against one’s own cells, resulting in inflammation, cell injury, or tissue/organ dysfunction.

Epidemiology

  • Most autoimmune diseases are more common in women than in men (2:1). 
  • Stress factors such as pregnancy or hormone disturbances may increase the chance of occurrence. 
  • Affects around 5%–10% of the U.S. population
  • Age at onset depends on the disease, as seen in the following:
    • Sjögren’s syndrome: around 40–60 years of age
    • Systemic lupus erythematosus (SLE): usually seen at 15–55 years of age (earlier onset → more severe form of SLE)
    • Systemic sclerosis: usually seen at 20–50 years of age
    • Rheumatoid arthritis: diagnosed at 30–60 years of age
  • Onset is also affected by subtle signs and symptoms that could be missed, thus delaying diagnosis.

Immunologic Tolerance

The immune system uses lymphocyte activation for defense against pathogens, but at the same time, maintains self-tolerance, which is unresponsiveness to one’s own antigens. Immunologic tolerance is protective and has different mechanisms (failure of which is a factor in autoimmunity).

Central tolerance

  • Clonal deletion (negative selection): 
    • This mechanism (in the thymus) is where the T cells reacting strongly to identified self-antigens are removed (by apoptosis).
    • Prevents release of dysfunctional T cells (that recognize self-antigens and can activate autoimmunity)
    • Facilitated by autoimmune regulator (AIRE) protein
  • Receptor editing: 
    • B cells undergo receptor gene rearrangements, expressing antigen receptors not specific for self-antigens.
    • If no receptor editing takes place, the B cells undergo apoptosis.

Peripheral tolerance

  • Clonal anergy: 
    • When self-antigens are recognized, lymphocytes become functionally unresponsive.
    • T cells:
      • Require 2 signals, the antigen and a costimulatory molecule, for activation
      • Without 2 signals, cells are anergic (alive but incapable of responding or functionally inactivated).
      • Costimulation helps avoid activation of T cells by benign antigens.
    • B cells become unable to respond when self-antigens are encountered in peripheral tissues.
  • Immunologic ignorance: T cell, which is viable and capable of responding, does not notice or is unaffected by the antigen.
  • Regulatory T cells: 
    • CD4+ T cells, expressing CD25 and FOXP3
    • Prevent excessive inflammation and tissue damage
    • Down-regulate activity of many immune cells
  • Apoptosis (clonal deletion): T cells that react to self-antigens receive signals to proceed with cell death:
    • Cells express BIM, a pro-apoptotic protein/initiator of the BCL2 family → apoptosis.
    • Cells express Fas (death receptor), a member of tumor necrosis factor (TNF) receptor family → apoptosis

Pathophysiology

Features of autoimmunity

Emergence of autoimmune disorders involves interaction of different factors (genetic, environmental, and immunologic), leading to activated immune response, with manifestations.

  • Autoreactivity:
    • Immune reaction (autoantibodies and/or excessive T-cell responses) specific for self-antigen or self-tissue:
      • Note that autoantibodies can be found in both healthy individuals and in injury, cancer, or infection.
      • Autoantibodies do not automatically indicate disease (manifestations need to be evident).
    • Can be triggered by infections:
      • Viruses such as HIV and EBV cause polyclonal B-cell activation → autoantibodies
      • Molecular mimicry: streptococcal proteins have sequences similar to those of proteins → ↑ antibodies → rheumatic heart disease
      • Infections can modify self-antigens through injury, creating neoantigens → activate T cells
      • Microbes can induce costimulators on antigen-presenting cells: If self-antigens are presented, self-reactive T cells are activated.
    • Other factors:
      • UV radiation leads to cell death → nuclear antigens exposed → immune response
      • Tissue injury → release of self-antigens → immune response
  • Clinical autoimmunity:
    • Signs and symptoms are recognized.
    • In many cases, serologic findings are positive before manifestations occur.
  • Genetic component:
    • Most autoimmune diseases are multigenic disorders:
      • Gene polymorphisms affect immune cell response.
      • But several gene polymorphisms are usually needed to affect autoreactivity.
    • Genes of the MHC or HLA: most prominent genetic susceptibility factor
    • Examples of non-HLA genes: polymorphisms in protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) (related to rheumatoid arthritis, type 1 diabetes), NOD2 (Crohn’s disease)
The development of autoimmune diseases

Multiple factors affect the development of autoimmune disease:
The combination of genetic susceptibility factors, the environment, and a defect in immunologic tolerance lead to activation of self-reactive lymphocytes and development of autoimmune disorders.

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Selected genes associated with autoimmune diseases

Table: Selected genes associated with autoimmune diseases
GenesAssociated autoimmune disease
MHC/HLAMost autoimmune diseases
PTPN22
  • Type 1 diabetes
  • Rheumatoid arthritis
  • Thyroid autoimmune diseases
  • Inflammatory bowel disease
CTLA4
  • Type 1 diabetes
  • Rheumatoid arthritis
  • Thyroid autoimmune disease
IL2RA
  • Type 1 diabetes
  • Multiple sclerosis
IL2/IL21
  • Type 1 diabetes
  • Rheumatoid arthritis
  • Inflammatory bowel disease
BLK
  • Rheumatoid arthritis
  • SLE

Pathogenetic mechanisms

  • Defect in immune tolerance: 
    • Can affect central or peripheral tolerance
    • Mutation involving AIRE → chronic mucocutaneous candidiasis or chronic mucocutaneous candidiasis (CMCC; autoimmune syndrome with chronic, noninvasive Candida infections)
    • Immunologic ignorance can be overcome by increased antigen availability.
  • Defect in active regulation: 
    • Regulatory T cells (Tregs) express FOXP3.
    •  Mutations involving FOXP3 → immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome
  • Defect in central and peripheral regulation of B cells: 
    • Autoreactive B cells are eliminated via various mechanisms or checkpoints (deletion, anergy, and receptor editing).
    • In SLE, aberrant checkpoints and increased autoreactive B cells have been noted. 
  • Cell surface and soluble antigens attacked:
    • Antigens on cell surfaces can be attacked by autoantibodies.
    • Examples:
      • Thyroid cell with surface thyroid-stimulating hormone (TSH) receptors → receptor stimulation (Graves’ disease)
      • Neuromuscular junctions with acetylcholine receptors → blockage (myasthenia gravis)
  • Innate immunity: 
    • Pattern recognition receptors (PRRs) are proteins (essential to innate immunity) that distinguish foreign material (e.g., microbes) from self.
    • Variant of NACHT (NAIP, CIITA, HET-E, and TP1) leucine-rich-repeat proteins (NALPs), a PRR, is associated with autoimmune conditions with vitiligo.
  • T cell-mediated injury: 
    • Cytotoxic T-cell response is generated.
    • PTPN22: affects the enzyme, which alters signaling in lymphocytes (T-cell hyperresponsiveness)
  • Formation of immune complexes: 
    • Immune complexes (ICs) result from a reaction between antibodies and antigens present on cell surfaces or in the circulation. 
    • Deposition in organs → immune response against the IC deposits → autoimmune disease

Major Autoimmune Diseases

Graves’ disease

  • Description: presence of circulating antibodies against the TSH receptors, leading to increased thyroid function
  • Autoimmune mechanism: 
    • Autoantibodies, most importantly thyrotropin receptor antibodies (TRAbs), are produced.
    • In 90% of cases, thyroid-stimulating immunoglobulins are noted.
    • Thyroid-stimulating immunoglobulins → mimic TSH receptor → release of thyroid hormones
  • Effect: hyperfunctioning thyroid gland (hyperthyroidism)

Rheumatoid arthritis

  • Description: chronic, progressive, autoimmune condition with symmetric, inflammatory polyarthritis
  • Autoimmune mechanism:
    • Activated CD4+ T cells → inflammatory mediators that cause tissue injury: 
      • Interferons and interleukins
      • TNF (most implicated, thus anti-TNF biologics are used for treatment)
    • B cells produce antibodies to citrullinated proteins (anti–citrullinated peptide antibodies (ACPAs), often tested as anti–cyclic citrullinated peptide).
  • Effects: 
    • Joint inflammation 
    • Structural damage in affected sites

Hashimoto’s disease

  • Description: autoimmune disease with destruction of the thyroid cells and thyroid failure
  • Autoimmune mechanism: 
    • Breakdown of immunologic tolerance to thyroid self-antigens (which include thyroid peroxidase (TPO), thyroglobulin, and TSH receptor) 
    • Cytotoxic T cells and cytokines destroy thyroid cells.
    • Antibodies to thyroglobulin (Tg) and TPO: secondary role in thyroid cell death but are markers of thyroid autoimmunity
    • Blocking-type TSH receptor antibodies also found
  • Effects: 
    • Lymphocytic infiltration of the thyroid (chronic lymphocytic thyroiditis)
    • Destruction of thyroid tissue → hypothyroidism

Sjögren syndrome

  • Description: infiltration of glandular tissues, such as the salivary and lacrimal glands, by lymphocytes
  • Autoimmune mechanism: 
    • Trigger may be a viral infection → cell death and release of tissue antigens
    • Aberrant lymphocytes (usually CD4+ T cells and B cells) infiltrate the glands.
    • Cytokines and autoantibodies → damage and atrophy the glands → ↓ exocrine production
    • Antibodies against 2 ribonucleoproteins are present in 60%–70% of cases: 
      • Anti-SSA/Ro antibodies
      • Anti-SSB/La antibodies
  • Effects:
    • Lymphocytic infiltration of lacrimal and salivary glands → ↓ secretory gland function
    • Other exocrine glands can be involved.

Multiple sclerosis

  • Description: chronic inflammatory autoimmune disease leading to demyelination of the CNS
  • Autoimmune mechanism: 
    • Exact mechanism unknown
    • T helper (Th) 1 and Th17 cells, react against myelin antigens → ↑ cytokines, macrophages, and other leukocytes → damage and cell death
  • Effects: 
    • Demyelination → neurologic deficits
    • Sites most likely affected:
      • Periventricular white matter
      • Optic nerve
      • Brain stem
      • Cerebellar peduncles
      • Corpus callosum
      • Spinal cord

Ankylosing spondylitis

  • Description: 
    • Chronic inflammation of the axial skeleton, with severe disease leading to fusion and rigidity of the spine
    • Strongly associated with HLA-B27 
  • Autoimmune mechanism: 
    • Innate immunity is triggered. 
    • GI microbes possibly invade the systemic circulation (due to disruption of the gut mucosal barrier).
    • Cells, cytokines and ILs are released → innate-like immune cells go to the joints and entheses.
  • Effects:
    • Enthesitis (inflammation at the site of ligament or tendon insertion into bone)
    • Chronic inflammation → syndesmophytes form → vertebral fusion

Type 1 diabetes

  • Description: metabolic disorder with hyperglycemia, due to insulin deficiency 
  • Autoimmune mechanism:
    • As with any autoimmune disease, genetics and the environment play a role.
    • Immunologic tolerance of T cells (specific for islet antigens) fails.
    • Can be a defect in regulatory T cells or clonal deletion
  • Effects:
    • Pancreatic β-cell destruction
    • Insulin deficiency → ↑ glucose

Systemic lupus erythematosus

  • Description: autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations.
  • Autoimmune mechanism:
    • Cell damage occurs from multifactorial triggers → ↑ exposure to nuclear antigens (DNA and RNA)
    • Autoreactive T and B cells are activated → production of autoantibodies:
      • ANAs
      • Anti–double-stranded DNA (anti-dsDNA) antibodies
      • Anti-Smith (anti-Sm) antibodies
      • Anti-histone antibodies
      • Anti-Ro and anti-La antibodies
      • Anti-ribonucleoprotein antibodies
      • Antiphospholipid antibodies
    • Perpetual T- and B-cell activation results in persistently ↑ antibody production → organ damage by:
      • Immune complex deposition (organs and vasculature)
      • Direct interaction with nuclear antigens → activating complement → cell injury and apoptosis 
  • Effects:
    • Inflammatory changes, notable in blood vessels, kidneys, connective tissue and skin, lead to organ damage and dysfunction.
    • Multisystem involvement causes variable clinical presentation.

Myasthenia gravis

  • Description: weakness and fatigability of skeletal muscles, usually associated with dysfunction/destruction of acetylcholine receptors (AchRs)
  • Autoimmune mechanism:
    • Antibodies against AchRs (noted in 85%) at the neuromuscular junction:
      • Either block acetylcholine binding or destroy the receptor sites
      • Block the action of muscle specific tyrosine kinase (MuSK), which is a transmembrane component of the neuromuscular junction
    • Some patients have associated thymomas (10%), which can present as paraneoplastic syndrome secondary to thymomas.
    • Some do not have antibodies against AchR or MuSK (antibody-negative myasthenia gravis):
      • Antibodies against lipoprotein-related protein 4 are present.
      • Lipoprotein-related protein 4 is present on the postsynaptic membrane and induces clustering of AChRs.
  • Effects:
    • Depletion of AchRs
    • Limitation of myofibers to respond to acetylcholine
    • Fluctuating weakness or fatigability that worsens with exertion through the course of the day

Management

The approaches used in the management of autoimmune diseases are: 

  • Replace missing component:
    • When inflammatory response is extensive and damage is irreversible
    • Seen in:
      • Type 1 diabetes: insulin
      • Hashimoto’s thyroiditis causing hypothyroidism: thyroid hormone therapy
  • Inhibition of function, such as in:
    •  Graves’ disease: thyroidectomy, antithyroid therapy, or radioactive iodine ablation
    • Myasthenia gravis: thymectomy, anticholinesterase inhibitors
  • Focus on preventing the actions of immune components (e.g., cells, cytokines): immunosuppressants (e.g., corticosteroids, biologic agents)

References

  1. Angum, F., Khan, T., Kaler, J., et al. (2020). The prevalence of autoimmune disorders in women: a narrative review. Cureus 12(5):e8094. https://doi.org/10.7759/cureus.8094
  2. Kumar, V., Abbas, A., Aster, J. (Eds.) (2021). Diseases of the immune system. In: Robbins and Cotran Pathologic Basis of Disease, 10th ed. Elsevier, pp. 215–234.
  3. Pisetsky, D. (2020). Overview of autoimmunity. UpToDate. Retrieved August 16, 2021, from https://www.uptodate.com/contents/overview-of-autoimmunity
  4. Rosenblum, M. D., Remedios, K. A., Abbas, A. K. (2015). Mechanisms of human autoimmunity. Journal of Clinical Investigation 125:2228–2233. https://doi.org/10.1172/JCI78088
  5. Smith, D.A., Germolec, D.R. (1999). Introduction to immunology and autoimmunity. Environ Health Perspect 107(Suppl 5):661–665. Retrieved August 17, 2021, from https://pubmed.ncbi.nlm.nih.gov/10502528/
  6. Zenewicz, L., Abraham, C., Flavell, R., Cho, J. (2010). Unravelling the genetics of autoimmunity. Cell 140:791–797. https://doi.org/10.1016/j.cell.2010.03.003

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