Autoimmunity

Question 1

What is autoimmunity?

Answer 1

• 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.

Question 2

pathological consequence of autoimmunity

Answer 2

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

Question 3

what is a self-antigen?

Answer 3

• 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

Question 4

Adaptive Immune Response Mediators of Autoimmunity: T cells

Answer 4

• 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

Question 5

Adaptive Immune Response Mediators of Autoimmunity: autoantibodies

Answer 5

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

Question 6

what is hypersensitivity?

Answer 6

• “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”

Question 7

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

Answer 7

Type II (3 different subtypes)
or Type III

Question 8

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

Answer 8

Type IV Hypersensitivity-like Reactions

Question 9

Autoimmune Diseases caused by Type II Hypersensitivity

Answer 9

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

Question 10

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

Answer 10

• 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)

Question 11

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

Answer 11

• 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)

Question 12

What is Autoimmune Hemolytic Anemia?

Answer 12

• 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

Question 13

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

Answer 13

• 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

Question 14

What is Pemphigus vulgaris?

Answer 14

• 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

Question 15

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

Answer 15

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

Question 16

What is Grave’s disease?

Answer 16

• 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

Question 17

What is Myasthenia Gravis?

Answer 17

• 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

Question 18

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

Answer 18

• 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

Question 19

What is Systemic Lupus Erythematosus?

Answer 19

• 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)

Question 20

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

Answer 20

• Hashimoto’s Thyroiditis
• Type 1 Diabetes
• Multiple Sclerosis

Question 21

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

Answer 21

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

Question 22

What is Hashimoto’s Thyroiditis?

Answer 22

• 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.

Question 23

What is Insulin-Dependent Diabetes Mellitus?

Answer 23

• 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

Question 24

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

Answer 24

• 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)

Question 25

what is multiple sclerosis?

Answer 25

- 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)

Question 26

susceptibility factors for autoimmune disease

Answer 26

- susceptibility genes - immune regulation - environment

Question 27

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

Answer 27

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

Question 28

Where is there Evidence for the existence of susceptibility genes?

Answer 28

- 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

Question 29

Autoimmune diseases are most strongly genetically linked to what genotypes?

Answer 29

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

Question 30

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

Answer 30

- 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

Question 31

Environmental factors that can play a role in disease

Answer 31

* Hormones * Infection * Traumatic injury

Question 32

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

Answer 32

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.

Question 33

What is Sjogren's Syndrome?

Answer 33

* 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

Question 34

Proposed Mechanisms for Initiation of Autoimmunity by Trauma or Infection

Answer 34

* 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

Question 35

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

Answer 35

- 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

Question 36

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

Answer 36

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

Question 37

What is molecular mimicry?

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

genes

Question 40

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

Answer 40

selectively downregulate the autoantigen-specific immune response while allowing the protective immune response to remain functional *treatment with antagonists against pro-inflammatory mediators

Question 41

therapeutic strategies for autoimmune disorders

Answer 41

* 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.