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Micro and Immuno > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

What is autoimmunity?

A
  • A situation in which the adaptive immune response
    reacts against its host, i.e., a failure in self-tolerance
  • Mediated by auto-reactive T cells and/or auto- antibodies.
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2
Q

pathological consequence of autoimmunity

A

autoimmune diseases: affect approximately
7% of human population, and are often chronically debilitating and can be fatal

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3
Q

what is a self-antigen?

A
  • Any molecule produced in the body that has antigenic properties
  • Includes all proteins (in humans, 30,000 - 100,000 candidates), nucleic acids, lipids, etc. and possibly even indigenous bacterial flora of the intestine
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4
Q

Adaptive Immune Response Mediators of Autoimmunity: T cells

A
  • Delayed Type Hypersensitivity (DTH) response (primarily mediated by Th1 CD4 cells)
  • Th17-mediated response (CD4 cells)
  • Cytotoxic response (CD8 cells)
  • T cell help (Th1 or Th2) in auto-antibody response
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5
Q

Adaptive Immune Response Mediators of Autoimmunity: autoantibodies

A
  • Complement-mediated target cell lysis and inflammation
  • Fc or complement receptor phagocytosis
  • Immune complex formation and deposition
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6
Q

what is hypersensitivity?

A
  • “state of altered reactivity in which the body reacts with an exaggerated immune response to what is perceived as a foreign substance”
  • “refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-
    sensitized (immune) state of the host”
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7
Q

Antibody-mediated autoimmune diseases are caused by which types of hypersensitivity reactions?

A

Type II (3 different subtypes)
or Type III

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8
Q

T cell-mediated autoimmune diseases are caused by what type of hypersensitivity reactions?

A

Type IV Hypersensitivity-like Reactions

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9
Q

Autoimmune Diseases caused by Type II Hypersensitivity

A
  • Autoimmune Hemolytic Anemia
  • Pemphigus vulgaris
  • Grave’s Disease
  • Myasthenia Gravis
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10
Q

Mechanisms in antibody-mediated autoimmune disease caused by a Hypersensitivity Type II-like Reaction

A
  • Opsonization and phagocytosis/complement- mediated lysis mechanisms (directed against cell-
    associated self-antigens)
  • Complement- and Fc receptor-mediated mechanism (directed against tissue self-antigens)
  • Autoantibody-mediated alteration of physiological responses (directed against receptors)
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11
Q

Describe Opsonization and phagocytosis/complement- mediated lysis mechanisms (directed against cell-
associated self-antigens)

A
  • antibody binds to the target cell so that phagocyte will phagocytose the cell
    OR
  • antibody directs complement to cause puncture and lysis of target cell (MAC)
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12
Q

What is Autoimmune Hemolytic Anemia?

A
  • Destruction of RBC resulting in anemia
  • oral manifestations include bleeding of tongue, pallor of palatal and gingival mucosa
  • Associated with anti-RBC antibodies; type II hypersensitivity response: Antibody mediated opsonization and phagocytosis and Complement-mediated lysis
  • Antigens: probably Rh or I antigen
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13
Q

Describe Complement- and Fc receptor-mediated mechanism (directed against tissue self-antigens)

A
  • tissue damage with complement and Fc receptor-mediated inflammation
  • antibodies aren’t directed specifically against a cell, but instead a tissue
  • antibodies bind to tissue antigen and trigger complement activation cascade
  • leads to leukocyte activation and tissue injury and inflammation
  • different from first subset because is directed against a tissue antigen rather than specific cells, causing an inflammatory response within the tissue
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14
Q

What is Pemphigus vulgaris?

A
  • Rare skin disorder characterized by blistering of skin and mucous membranes, involves painful sores and blisters on skin and in mouth, can be fatal if untreated
  • oral lesions precede skin lesions by weeks to months in 80% of cases
  • Auto-antibodies against proteins in the desmosomes in epidermis; type II hypersensitivity response: actual mechanism is unknown
  • Antigens: Desmosomes 1 & 3
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15
Q

Describe Autoantibody-mediated alteration of physiological responses (directed against receptors)

A
  • autoantibody binds to a receptor and elicits a physiological response that’s different from an inflammatory response
  • stimulating or inhibiting
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16
Q

What is Grave’s disease?

A
  • Overstimulation of thyroid resulting in hyper-thyroidism
  • oral manifestations include increased caries and susceptibility to periodontal disease, accelerated dental eruption, maxillary and mandibular osteroporosis, etc.
  • Associated with anti-thyroid stimulating hormone receptor (TSHR) auto-antibodies: Auto-antibodies act as agonists and stimulate thyroid to overproduce thyroid hormone in response to TSHR signaling
  • Antigen: Thyroid stimulating hormone receptor
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17
Q

What is Myasthenia Gravis?

A
  • Blockage of neuromuscular transmission resulting in progressive muscular weakness; oral issues include, difficulty with mastication, etc
  • Associated with anti-acetylcholine receptor (AChR) auto-antibodies: Auto-antibodies act as antagonists and block binding of acetylcholine possibly by inducing internalization and degradation of AChR. Auto-antibodies also induce complement-mediated lysis of muscle cells.
  • Antigen: Acetylcholine receptor
18
Q

Describe Antibody-mediated autoimmune disease caused by a Hypersensitivity Type III-like Reaction

A
  • autoantibody binds to ubiquitous antigens floating throughout the blood stream/body fluids, creating large complexes that can then deposit in tissue
  • antigen specificity is floating around
  • complexes lodge in vascular tissue and then attract neutrophils and cause production of inflammatory cytokines and chemokines
19
Q

What is Systemic Lupus Erythematosus?

A
  • Immune complex deposition causes vasculitis and glomerulo-nephritis leading to rashes, arthritis, and severe kidney damage; oral issues, oral lesions.
  • Associated with auto-antibodies against a wide variety of ubiquitous cellular components: Form complexes with abundant antigen, deposit along
    walls of small blood vessels and activate complement system. Antibody production driven by T cell help
  • Antigens: Nucleic acids, histones, ribosomes (common components of cells throughout the bloodstream)
20
Q

Autoimmune Diseases caused by Type IV Hypersensitivity
(T cell-mediated)

A
  • Hashimoto’s Thyroiditis
  • Type 1 Diabetes
  • Multiple Sclerosis
21
Q

Describe T cell-mediated autoimmune diseases caused by Type IV Hypersensitivity-like Reactions

A

Two different ways:
1. CD4 cell becomes activated and produces cytokines that produce inflammation and tissue damage
2. CD8 cell response: directly kills individual cells

22
Q

What is Hashimoto’s Thyroiditis?

A
  • Damage to thyroid results in hypothyroidism
  • oral manifestations include, compromised peridontal health, delayed dental eruption, enamel hypoplasia in dentitions, etc
  • Associated with anti-thyroid auto- antibodies and DTH-mediating CD4 T cells: Infiltrating lymphocytes and macrophages cause tissue destruction; type IV hyper- sensitivity response. Autoantibodies may interfere with iodine uptake, therefore, result in further decreases in thyroid hormone production
  • Antigens: probably thyroglobulin and thyroid peroxidase.
23
Q

What is Insulin-Dependent Diabetes Mellitus?

A
  • Type I or juvenile diabetes - destruction of pancreatic beta cells resulting in decreased production of insulin and increased levels of blood glucose; oral issues include increased susceptibility to periodontal diseases, caries and tooth loss, salivary gland dysfunction, oral fungal and bacterial infections and increased incidence of oral mucosal lesions
  • Associated with anti-pancreatic T cells and auto-antibodies
  • Antigens: Insulin, GAD-65, probably others
24
Q

Auto-pancreatic T cells and auto-antibodies of Type I diabetes

A
  • Cytotoxic CD8 T cells may be required to initiate response
  • DTH-mediating (CD4) T cells also appear to be involved.
  • Involvement of auto-antibodies unknown
  • strongly directed against insulin producing cells only (beta cells)
25
Q

what is multiple sclerosis?

A
  • Inflammatory lesions in myelin sheath results in de-myelination, and leads to neurologic dysfunction and possibly paralysis; oral issues, impairment of good dental hygiene (can’t grab toothbrush)
  • Associated with anti-myelin T cells (Th1and/or Th17 and possibly CD8 cells): Infiltration of activated T cells and macrophages into
    brain and spinal cord; type IV- like
  • Antigens: Myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG)
26
Q

susceptibility factors for autoimmune disease

A
  • susceptibility genes
  • immune regulation
  • environment
27
Q

The cause(s) of most autoimmune diseases is very complex and likely requires…

A

multiple “hits” (both genetic and environmental); some autoimmune diseases are caused by a single gene mutation

28
Q

Where is there Evidence for the existence of susceptibility genes?

A
  • for many autoimmune diseases including type I diabetes (T1D), arthritis, MS, SLE: A concordance of 30-50% found in monozygotic twins versus 5% in dizygotic twins for T1D
  • Evidence for both genetic and environmental factors
29
Q

Autoimmune diseases are most strongly genetically linked to what genotypes?

A

specific MHC (HLA) genotypes: Primarily associated with MHC Class II, but also MHC Class I in certain diseases

Ex: DQ2 and DQ8 HLA allele individuals have a 25% increased risk of developing Type I diabetes, while those with DQ6 have a decreased chance

30
Q

Why must non-MHC factors also be involved in potential susceptibility genes?

A
  • since siblings with identical MHC have a lower incidence of autoimmune disease than identical twins
  • Non-MHC candidate genes that are (weakly) associated with autoimmune disease have been identified and are mostly related to immune function, e.g., cytokines and chemokines and their receptors, co-stimulatory and inhibitory molecules, molecules involved in innate immunity, transcription factors, etc.
  • multiple genetic “hits” needed for disease
31
Q

Environmental factors that can play a role in disease

A
  • Hormones
  • Infection
  • Traumatic injury
32
Q

What’s the theory behind why females are at greater risk of developing most autoimmune diseases?

A

In general, female sex steroids (estrogens) tend to be immuno- enhancive, and male sex steroids (androgens) tend to be immunosuppressive - therefore hormones may play a role in some
types of autoimmune diseases.

33
Q

What is Sjogren’s Syndrome?

A
  • Inflammation of the lacrimal and salivary glands. Characterized by dry eyes and mouth, and severe dental cavities
  • Mechanism is unknown, but is associated with infiltrating T cells and auto-antibodies
  • Very high incidence in women
34
Q

Proposed Mechanisms for Initiation of Autoimmunity by Trauma or Infection

A
  • Release of sequestered antigens - through trauma or infection.
  • Inappropriate class II expression - by non-professional APC exposed to an inflammatory response induced by an infectious agent.
  • Activation/migration of APC in target organ - via infection and inflammatory responses.
  • Molecular mimicry - cross-reaction between pathogen antigen and self-antigen.
  • Many, if not most, autoimmune diseases may, therefore, be triggered by inflammatory responses to infectious agents in genetically susceptible individuals; oral issues, individuals with autoimmune disease have higher plaque index
35
Q

Describe the Initiation of Autoimmunity through Trauma-induced Release of Sequestered Antigens

A
  • trauma to one eye results in the release of sequestered intraocular protein antigens
  • released intracocular antigens are carried to lymph nodes and activate T cells
  • effector T cells return via bloodstream and attack antigen in both eyes
  • Sympathetic ophthalmia
36
Q

Describe Initiation of Autoimmunity through inflammation- induced inappropriate expression of Class II

A

Ex:
- thyroid cells do not normally express HLA class II molecules
- IFNg produced during infection or nonspecific inflammation induces HLA class II expression on thyroid cells
- activated T cells recognize thyroid peptides presented by HLA class II and induce autoimmune thyroid disease

37
Q

What is molecular mimicry?

A

A microbe shares an immunologic epitope with the host (an epitope is a piece of an antigen that is recognized by the immune system). Antibodies cross-react

  • ex: some strands of strep have antigens that look like those on our heart, causing rheumatic fever
38
Q

1st and 2nd “hit” for pathogenic mechanisms of autoimmune disease

A

1st hit: susceptibility genes and failure of self-tolerance
2nd hit: infection, injury leading to tissue injury and autoimmune disease

39
Q

What ultimately determines if and which autoimmune diseases will be initiated?

A

genes

40
Q

Goal for therapy for the treatment of autoimmune diseases is to…

A

selectively downregulate the autoantigen-specific immune response while allowing the protective immune response to remain functional

*treatment with antagonists against pro-inflammatory mediators

41
Q

therapeutic strategies for autoimmune disorders

A
  • Depletion of lymphocytes (anti-CD20 for B cells).* Induction and/or transfer of antigen-specific regulatory T cells.
  • Delivery of immunosuppressive cytokines (IL-10, TGFβ) to prevent T cell activation or inhibit inflammation.
  • Delivery of deletion (apoptosis-inducing) signals (e.g., FasL) to activated auto-reactive T cells.
  • Induction of anergy in naive potentially autoreactive T cells.

Micro and Immuno (17 decks)

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