Tolerance, autoimmunity, and autoimmune diseases Flashcards
What are the two broad groups of autoimmune diseases?
- Systemic diseases
- Organ-specific diseases
What are the causes of autoimmune diseases?
- Genetic predisposition (commonly involving HLA genes)
- Environmental influences
Which organs are affected by SLE?
- Joints: arthritis
- Skin: butterfly rash on the face
- Kidneys: inflammation
- Blood cells
- Heart: pericarditis
- Lungs: pleurisy
Which genes are particularly important in the pathogenesis of SLE?
- C1q, C2, and C4
- FCGRIIB (for the IgG receptor FCγRIIb)
How does SLE develop, from an immune perspective?
- B cells form autoantibodies nad present autoantigens for activation of autoreactive T cells
- T cells participate through co-stimulator-mediated signaling pathways and secretion of cytokines
- Innate immunity participates through a TLR on certain pDCs that can be activated by the autoimmune complex, inducing production of IFN-α and the formation of NETs
What are the phases in the pathogenesis of SLE?
- Loss of adaptive immune tolerance leads to an increase in autoreactive B cells
- Signals from self-antigens, TLR ligands, BAFF/APRIL, and T cell-derived cytokines promote the formation of germinal centers and production of autoantibodies
- Innate immune defects lead to increased availability of self-antigens, including increased NETosis, impaired clearance of apoptotic debris, and reduced phagocytosis
How is the immune system implicated in type 1 diabetes?
- Decreased efficiency of negative selection of T cells, either due to altered tissue-specific antigen expression or due to TCR signaling, allows for the increased escape of pancreatic β cell-specific T cells
- β cell-specific Foxp3+ Treg development may be suboptimal due to dysregulation of TCR signaling
- β cell-specific T cells are stimulated in the pancreatic lymph nodes by APCs, leading to effector T cell formation. These effector T cells drive inflammation in the pancreatic islets
- Ongoing islet inflammation also leads to generation of new autoantigens either directly in β cells or during antigen processing by APCs
What is Grave’s disease?
An autoimmune disease affecting the thyroid where autantibodies against the thyroid stimulating hormone (TSH) receptor act as agonists and induce hyperthyroidism and goiter
What are the symptoms of Grave’s disease?
- Sweating
- Exophthalmos
- Goiter
- Arrythmia and tachycardia
- Nausea and diarrhea
- Tremor
What are examples of autoantigens associated with SLE?
- Nucleolin
- Ku
- Lamins
What are the types of self-tolerance?
- Central tolerance: induced in immature self-reactive lymphocytes in the generative lymphoid organs, ensuring that the repertoire of mature lymphocytes is incapable of responding to self antigens
- Peripheral: induced in mature lymphocytes in peripheral sites, preventing activation of self-reactive lymphocytes that managed to evade central tolerance measures
What are the mechanisms of central T cell tolerance?
- Negative selection: deletion of T cells that react strongly to self-antigens by apoptosis
- Development of these T cells into reuglatory T cells that do not perform immune-stimulating effector functions and promote peripheral tolerance
How are T cells exposed to a wide repertoire of antigens while in the thymus?
The thymic epithelium expresses many protein antigens that are typically present only in certain peripheral tissues by the function of autimmune regulator (AIRE) protein
What disease is associated with mutations in the AIRE gene?
Autoimmune polyendocrine syndrome type 1 (APS1)
What are the features of autoimmune polyendocrine syndrome type 1?
Antibody- and lymphocyte-mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic islets
What are the mechanisms of peripheral T cell tolerance?
- Anergy: lack of costimulation leads to functional unresponsiveness
- Suppression by regulatory T cells
- Deletion by apoptosis
How is anergy stimulated in T cells?
- Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immune signals may make the cells incapable of responding
- Full activation of T cells requires both antigen recognition by the TCR and recognition of costimulators, mainly B7, by CD28. Prolonged TCR stimulation without a costimulatory signal may lead to anergy
- TCR-induced signal transduction is blocked in anergic cells by an unknown mechanism
- When T cells recognize self antigens, they may engage inhibitory CD28 receptors, terminating T cell response
What are the inhibitory signaling molecules of T cells?
- CTLA-4: a CD28 receptor family member that binds to B7. This receptor blocks B7 molecules from binding to stimulatory receptors. Expressed on activated CD4+ cells
- PD-1: has an ITIM (immunoreceptor tyrosine-based inhibition motif) that delivers inhibitory signals from self antigens and some viral antigens. Expressed on activated CD4+ and CD8+ cells
How is apoptosis induced in T cells as part of peripheral tolerance?
- Insufficiency of survival signals (namely IL-2) leads to apoptosis by the intrinsic pathway
- Engagement of death receptors leads to apoptosis by the extrinsic pathway (Fas–FasL)
How do regulatory T cells function in peripheral T cell tolerance?
- Production of the immunosuppressive cytokines IL-10 and TGF-β
- Reduced ability of APCs to stimulate T cells—the Treg cells bind B7 molecules on APCs using CTLA-4, reducing the costimulation of T cells
- Consumption of IL-2, leading to apoptosis of T cells. This happens since Treg cells have high expression of IL-2 receptors
What are the mechanisms of central B cell tolerance?
- Receptor editing: moderate or strong binding of self-antigens in the bone marrow leads to reactivation of RAG1 and RAG2 and VJ recombination of the other Ig κ locus
- Deletion by apoptosis of self-reactive B cells
- Anergy: if developing b cells recognize self antigens weakly, the cells become functionally unresponsive and exit the bone marrow in this unresponsive state. Anergy is due to downregulation of BCR expression as well as a block in BCR signaling
What are the mechanisms of peripheral B cell tolerance?
- Anergy and deletion: some self-reactive B cells that are repeatedly stimulated by self antigens become unresponsive to further activation. These B cells may also be eliminated by Fas–FasL apoptosis (FasL on helper T cells, Fas on the B cell)
- Engagement of inhibitory receptors lead to blockade of the effector functions of self-reactive B cells
What are the mechanisms that lead to tolerance of commensal microbe antigens?
- An abundance of IL-10–producing Treg cells
- An unusual strain of dendritic cells in the intestines that respond to TLR engagement by being inhibited, not activated
How are fetal antigens tolerated?
The generation of peripheral FoxP3+ Treg cells for paternal antigens
What are the factors that lead to the pathogenesis of autoimmune diseases?
- Inheritance of susceptibility genes
- Environmental triggers, such as infections
One theory proposes that susceptibility genes interfere with self-tolerance and lead to generation of many self-reactive T cells and B cells. Environmental stimuli then cause cell and tissue injury, leading to increased presentation of self-antigens and generation of effector self-reactive T cells and autoantibodies
Which genes contribute most to autoimmune diseases?
MHC genes
Which autoimmune diseases are associated with certain MHC alleles?
- Ankylosing spondylitis
- Rheumatoid arthritis
- Type 1 diabetes mellitus
- Pemphigus vulgaris
Which autoimmune diseases re associated with defects in the CTLA4 gene?
- Autosomal dominant immune dysregulation syndrome
- Type 1 diabetes mellitus
- Rheumatoid arthritis
Which autoimmune diseases are associated with defects in the FOXP3 gene?
- Immune dysregulation
- X-linked polyendocrinopathy and enteropathy (IPEX)
Which autoimmune disease is associated with defects in the FAS gene?
Autoimmune lymphoproliferative syndrome (ALPS)
Which autoimmune disease is associated with defects in the PTPN22 gene?
Rheumatoid arthritis
Which autoimmune disease is associated with defects in the NOD2 gene?
Crohn disease
Which autoimmune diseases are associated with defects in the IL23R gene?
- Inflammatory bowel disease
- Psoriasis
- Ankylosing spondylitis
Which autoimmune diseases are associated with defects in the CD25 gene?
- Multiple sclerosis
- Type 1 diabetes
Defects in which gene are associated with multiple sclerosis?
CD25
Defects in which genes are associated with type 1 diabetes?
- CD25
- MHC
- CTLA4
Defects in which genes are associated with inflammatory bowel disease?
- NOD2 (Crohn disease)
- IL23R
Defects in which gene are associated with rheumatoid arthritis?
- PTPN22
- MHC
- CTLA4
How do infections contribute to autoimmune disease?
- An infection in a tissue may induce a local innate immune response, leading to increased production of costimulators and cytokines (especially type I IFNs) by APCs, potentially activating self-reactive T cells
- Some infectious microbes may produce peptide antigens that are similar to, and cross-react with, self antigens. Immune responses to these microbial peptides may result in autoimmune atacks (molecular mimicry)
