Autoimmunity

Author(s): and

Learning outcomes

By the end of this CAL you will be able to:

  • Describe the pathogenesis of different types of autoimmune disease
  • Recognise the clinical manifestations of specific examples

Introduction Part 1 of 10

Autoimmune diseases are caused by immunity misdirected at healthy cells and tissues – an immune reaction against “self”.

The main paradigm behind autoimmunity is a failure of self-tolerance due to:

  • Genetic susceptibility
  • Environmental triggers

Tolerance

©Gwilz [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons
Proposed mechanisms of immunosuppression by regulatory T cells include: production of immunosuppressive IL-10, IL-35 and TGFβ (some TGFβ is membrane-bound); production of cytolytic granzyme B; TIGIT-mediated DC production of IL-10 and TGFβ; LAG3 mediated down-regulation of DC function; CTLA4 preventing co-stimulation by by CD80 and CD86 through CD28; inducing expression of IDO by DCs; the cell surface ectoenzymes CD39 and CD73 producing immunosuppressive adenosine; starving effector cells of IL2 through high affinity uptake by regulatory T cell IL2 receptors; inducing IL-10 production by non-regulatory T cells. Abbreviations: CD = cluster of differentiation; DC = dendritic cell; IL = interleukin; TGFβ = transforming growth factor beta; IL2R = IL2 receptor; TIGIT = T cell immunoreceptor with Ig and ITIM domains; LAG-3 = lymphocyte-activation gene 3; IDO = indoleamine 2,3-dioxygenase; CTLA4 = cytotoxic T lymphocyte antigen 4; MHCII = major histocompatibility complex II.

Genetic risk factors Part 2 of 10

Autoimmune diseases are complex multigenic disorders. Predisposition can be conferred by:

  • Major histocompatibility complex (MHC)
  • Non-MHC genes –
    • NOD2 (Crohn’s disease)
    • PTPN22 – Insulin dependent diabetes mellits (IDDM)
Disease HLA serotype Relative risk
Ankylosing spondylitis B27 90
Goodpasture’s syndrome B27 10
Grave’s disease DR3 4
Myasthenia gravis DR3 2.5
SLE DR3 6
IDDM DR3/4 3
Rheumatoid arthritis DR4 4

Factors initiating autoreactivity Part 3 of 10

Infection

  • The release of sequestered antigen
  • Upregulation of costimulators on APCs

T cell bypass

Tolerance bypassed by:

  • Modification: neoantigen generated by binding of a pathogen to a self-component
  • Inflammation: immunostimulatory environment activates self-reactive T cells
  • Molecular mimicry: antibodies or T cells generated in response to infection cross-react with self

Molecular mimicry Part 4 of 10

Antibodies or T cells, generated in response to infection, can cross-react with self-targets.

©David Dorward, University of Edinburgh 2017 CC BY-SA
Molecular mimicry leading to autoimmune disease.

Characteristics of autoimmune diseases Part 5 of 10

Civil war: The immune system seems to be attacking cells and tissues as if they were infected.

General features:

  • Chronic disease with relapse and remission
  • Clinical symptoms shaped by the nature of the immune response

[Autoantigens – antigens on target tissues. Autoantibodies – antibodies to autoantigens.]

Spectrum of disease

Autoimmune diseases can range from highly organ-specific to systemic, largely depending on the distribution of the autoantigen.

©David Dorward, University of Edinburgh 2017 CC BY-SA
Autoimmune disease spectrum.

Mechanisms of autoimmunity Part 6 of 10

Antibody-mediated

Type II reactions.

  • Grave’s disease
  • Myasthenia gravis

Immune complex-mediated

Type III reactions.

  • Systemic lupus erythematosus (double-stranded DNA)

T cell-mediated

Type IV-mediated

  • Insulin-dependent diabetes mellitus (IDDM)
  • Rheumatoid arthritis

Antibody mediated autoimmunity Part 7 of 10

Grave’s disease

Grave’s disease is a good example of antibody-mediated autoimmune disease.

IgG antibodies against thyroid stimulating hormone (TSH) receptor act to stimulate thyroxine release.

©David Dorward, University of Edinburgh 2017 CC BY-SA
Mechanism of Grave’s disease.

Symptoms are caused by excessive thyroxine:

  • Nervousness
  • Heat intolerance
  • Bulging eyes
  • Tremor
  • Tachycardia
  • Weight loss
© Jonathan Trobe, M.D. - University of Michigan Kellogg Eye Center CC BY 3.0
Thyroid eye disease showing proptosis and lid retraction.

Myasthenia gravis

Myasthenia gravis is caused by antibodies against the acetylcholine receptor. It is associated with thymic abnormalities.

©Elliejellybelly13 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons
Muscles will contract or relax when they receive signals from the nervous system. The neuromuscular junction is the site of the signal exchange. The steps of this process in vertebrates occur as follows:(1) The action potential reaches the axon terminal. (2) Voltage-dependent calcium gates open, allowing calcium to enter the axon terminal. (3) Neurotransmitter vesicles fuse with the presynaptic membrane and ACh is released into the synaptic cleft via exocytosis. (4) ACh binds to postsynaptic receptors on the sarcolemma. (5) This binding causes ion channels to open and allows sodium and other cations to flow across the membrane into the muscle cell. (6) The flow of sodium ions across the membrane into and potassium ions out of the muscle cell generates an action potential which travels to the myofibril and results in muscle contraction. Labels:A: Motor Neuron Axon; B: Axon Terminal; C. Synaptic Cleft; D. Muscle Cell; E. Part of a Myofibril.
©Elliejellybelly13 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons
In myasthenia gravis, autoantibodies destroy the nicotinic acetylcholine receptor, or a related protein called MuSK a muscle-specific kinase such that post-synaptic signalling and muscle contraction are impeded. A: Motor Neuron Axon B: Axon Terminal C. Synaptic Cleft D. Muscle Cell<br />E. Part of a Myofibril

Symptoms include:

  • Muscle weakness
  • Shortness of breath
  • Drooping eyelids (ptosis)
  • Double vision (diplopia)
  • Unstable gait
By Mohankumar Kurukumbi, Roger L Weir, Janaki Kalyanam, Mansoor Nasim, Annapurni Jayam-Trouth. [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons
Photograph of a patient showing right partial ptosis. The left lid shows compensatory pseudo lid retraction because of equal innervation of the levator palpebrae superioris.

Immune complex mediated Part 8 of 10

Systemic lupus erythematosus

SLE is caused by the production of autoantibodies:

  • Antinuclear antibodies (ANA)
  • Antiphospholipid antibodies

Circulating immune complexes form and deposit in various organs/tissues to induce clinical symptoms.

Failure of tolerance

  • Genetic factors – MHC / non-MHC genes
  • Immunologic factors –
    • Failure in self-tolerance in B and T cells
    • Nuclear DNA and RNA bind receptors
    • Cytokines
  • Environmental factors –
    • Exposure to ultraviolet light
    • Gender (female > male)
    • Drugs
©2015 Gottschalk, Tsantikos and Hibbs. CC BY 4.0
Inflammation is a key factor in the pathogenesis of lupus. A hallmark of lupus is the presence of hyperactive B cells and loss of B-cell tolerance. Immune complexes containing nucleic acid autoantigens can engage and activate endosomal TLRs and promote inflammation in SLE. Plasma cell expansion and the production of autoantibodies are also features, although the autoantibodies are benign unless generated in an inflammatory milieu, wherein class-switching to pathogenic isotypes occurs. Proinflammatory cytokines not only drive T-cell activation and dendritic cell maturation, but they can stimulate extramedullary hematopoiesis leading to expansion of innate immune cells, and they can induce the production of acute-phase proteins (APPs). Autoantibodies become deposited in tissues such as the glomeruli of the kidney, leading to the activation of myeloid effector cells via Fcγ and complement receptors, leading to tissue destruction. Numerous factors, including genetic makeup, environment, diet, and stress, can modify disease course and severity. From: https://openi.nlm.nih.gov/detailedresult.php?img=PMC4623412_fimmu-06-00550-g001&req=4

Immune complex deposition, DNA-antiDNA complexes cause:

  • Vasculitis
  • Glomerulonephritis
  • Pericarditis
  • Butterfly rash
  • Arthritis
  • Pleural effusions
CNX OpenStax CC BY 4.0
Clinical features in systemic lupus erythematosus.

T cell mediated Part 9 of 10

Rheumatoid arthritis

Rheumatoid arthritis is a multi-organ disease mainly affecting joints.

It is caused by CD4+ T helper cells reacting to synovial joint antigens:

  • Bone resorption (RANKL)
  • Stimulate other effector cells –
    • Neutrophils, monocytes (IL-17)
    • Macrophages (IFNγ)
    • Synovial cells release proteases
©David Dorward, University of Edinburgh 2017 CC BY-SA
Pathogenesis of rheumatoid arthritis.

Summary Part 10 of 10

Antibody to cell-surface or matrix antigens ‘type II’

Disease Autoantigen Consequence
Autoimmune haemolytic anaemia Rh blood group antigens Destruction of RBC
Graves’ disease TSH receptor Hyperthyroidism
Myasthenia gravis Acetylcholine receptor Progressive weakness
Goodpasture’s syndrome Collagen type IV Glomerulonephritis

Immune complex disease ‘type III’

Disease Autoantigen Consequence
Subacute bacterial endocarditis Bacterial antigen Glomerulonephritis
Systemic lupus erythematosus DNA, histones, Ribosomes, snRNP, scRNP Glomerulonephritis, vasculitis, arthritis

T cell-mediated ‘type IV’

Disease Autoantigen Consequence
Type I diabetes (IDDM) Pancreatic b cell antigen b- cell destruction
Rheumatoid arthritis (RA) Synovial joint antigens Joint inflammation and destruction
Multiple sclerosis Myelin basic protein, proteolipid protein Brain degeneration, paralysis