Autoimmunity Flashcards
What is autoimmunity?
- 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.
pathological consequence of autoimmunity
autoimmune diseases: affect approximately
7% of human population, and are often chronically debilitating and can be fatal
what is a self-antigen?
- 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
Adaptive Immune Response Mediators of Autoimmunity: T cells
- 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
Adaptive Immune Response Mediators of Autoimmunity: autoantibodies
- Complement-mediated target cell lysis and inflammation
- Fc or complement receptor phagocytosis
- Immune complex formation and deposition
what is hypersensitivity?
- “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”
Antibody-mediated autoimmune diseases are caused by which types of hypersensitivity reactions?
Type II (3 different subtypes)
or Type III
T cell-mediated autoimmune diseases are caused by what type of hypersensitivity reactions?
Type IV Hypersensitivity-like Reactions
Autoimmune Diseases caused by Type II Hypersensitivity
- Autoimmune Hemolytic Anemia
- Pemphigus vulgaris
- Grave’s Disease
- Myasthenia Gravis
Mechanisms in antibody-mediated autoimmune disease caused by a Hypersensitivity Type II-like Reaction
- 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)
Describe Opsonization and phagocytosis/complement- mediated lysis mechanisms (directed against cell-
associated self-antigens)
- 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)
What is Autoimmune Hemolytic Anemia?
- 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
Describe Complement- and Fc receptor-mediated mechanism (directed against tissue self-antigens)
- 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
What is Pemphigus vulgaris?
- 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
Describe Autoantibody-mediated alteration of physiological responses (directed against receptors)
- autoantibody binds to a receptor and elicits a physiological response that’s different from an inflammatory response
- stimulating or inhibiting
What is Grave’s disease?
- 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
What is Myasthenia Gravis?
- 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
Describe Antibody-mediated autoimmune disease caused by a Hypersensitivity Type III-like Reaction
- 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
What is Systemic Lupus Erythematosus?
- 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)
Autoimmune Diseases caused by Type IV Hypersensitivity
(T cell-mediated)
- Hashimoto’s Thyroiditis
- Type 1 Diabetes
- Multiple Sclerosis
Describe T cell-mediated autoimmune diseases caused by Type IV Hypersensitivity-like Reactions
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
What is Hashimoto’s Thyroiditis?
- 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.
What is Insulin-Dependent Diabetes Mellitus?
- 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
Auto-pancreatic T cells and auto-antibodies of Type I diabetes
- 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)
what is multiple sclerosis?
- 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)
susceptibility factors for autoimmune disease
- susceptibility genes
- immune regulation
- environment
The cause(s) of most autoimmune diseases is very complex and likely requires…
multiple “hits” (both genetic and environmental); some autoimmune diseases are caused by a single gene mutation
Where is there Evidence for the existence of susceptibility genes?
- 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
Autoimmune diseases are most strongly genetically linked to what genotypes?
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
Why must non-MHC factors also be involved in potential susceptibility genes?
- 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
Environmental factors that can play a role in disease
- Hormones
- Infection
- Traumatic injury
What’s the theory behind why females are at greater risk of developing most autoimmune diseases?
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.
What is Sjogren’s Syndrome?
- 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
Proposed Mechanisms for Initiation of Autoimmunity by Trauma or Infection
- 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
Describe the Initiation of Autoimmunity through Trauma-induced Release of Sequestered Antigens
- 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
Describe Initiation of Autoimmunity through inflammation- induced inappropriate expression of Class II
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
What is molecular mimicry?
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
1st and 2nd “hit” for pathogenic mechanisms of autoimmune disease
1st hit: susceptibility genes and failure of self-tolerance
2nd hit: infection, injury leading to tissue injury and autoimmune disease
What ultimately determines if and which autoimmune diseases will be initiated?
genes
Goal for therapy for the treatment of autoimmune diseases is to…
selectively downregulate the autoantigen-specific immune response while allowing the protective immune response to remain functional
*treatment with antagonists against pro-inflammatory mediators
therapeutic strategies for autoimmune disorders
- 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.
