16 - Tolerance, Autoimmunity, and Transplantation Flashcards
Antigen sequestration
tissue specific antigen that are expressed in certaint sites (like the anterior chamber and lese of the eye), are partially isolated from most lymphocytes and inflammatory mediators, and thereby evade the immune system.
Central tolerance
occurs in primary lymphoid organs, where many self.reactive lymphoctes are eliminated before they can mature, and others are selected (at least in the thymus) to later engage in immune inhibitory responses targetinf self-Ags at tissue sites, protecting against autoimmunity
factors that promote tolerance rather than stimulation of the immun system by a given antigen
- fetal exposure
- high doses of Ag
- Long-term persistence of Ag in the host
- intravenous or oral introduction
- absence of adjuvants
- low levels of costimulation
- presentation of Ag by immature or inactivated APCs
- need for coordination between different immune cell types.
Peripheral tolerance
Peripheral tolerance processes occur after lymphocyte development, when immune cells are induced to act as inhibitors of self reactivity for Ag that is presented in a nonimmunogenic context.
Immune cells that inhibit immune responses against self
Tregs
Bregs
Treg cells, which inhibit immune reactivity against their cognate Ag int he periphery, can be CD4+ or CD8+, and typically express CD25 (IL-2R α chain), CTLA-4 (coinhibitory receptor), plus the master regulator TF FoxP3
Regulatory T cells dampen immune responses by inhibiting, decommissioning, or killing other immune cells that respond to their cognate Ag, including T cells, B cells and pAPCs. They do this through immune-suppressing cytokines (IL-10, TGF-β, IL-35), expression of inhibitory surface molecules (like CTLA-4), absorbing local IL-2 (with CD25), and via cellular cytotoxicity.
Regulatory populations og B cells (Bregs) and macrophages (MDSCs) can also suppress inflammation, often by secreting compounds like IL-10 and by acting as immune-inhibiting APCs.
MDSCs = myeloid-derived supressor cells.
Bregs have also been shown to supress inflammatory immune cascades associated with IL-1.
B10 cells
B cells that produce only the cytokine IL-10. Suppress or regulate immune response
Hashimoto’s Thyroiditis
Organ specific
the individual produces Abs and sensitized TH! cells specific for thyroid antigens.
targeted proteins: thyroglobulin and thyroid peroxidase
Abs binding to these proteins interferes with iron uptake, leading to decreased thyroid function and hypothyroisism (decreased roduction of thyroid hormones).
Leads to organ destruction (lymphocytes, macrophages and plasma cells infiltrate), hypothyroidism and inflammatory accumulation. More common in women, no one knows exactly why
Type 1 Diabetes
organ-specific
aka insulin dependent diabetes mellitis (IDDM)
caused by immune attack on insulin-producing cells (beta cells) in pancreas
the disease begins with cytotoxic T lymphocyte infiltration and activation of macrophages, which leads to cell mediated DTH response. results in cytokine release and the production of Abs.
most common therapy is daily administration of insulin to the affected individual.
Myasthenia Gravis
Tissue specific
mediated by blocking Abs.
produces auto-Abs that bind Acetyl-Choline (a neurotransmitter) receptors (AChR) on the motor end plates of muscles, blocking normal binding og acetylcholine, resulting in progressive weakening of the skeletal muscles. Abs cause the lysis of the cells bearing the receptors.
treatment: increasing acetylcholine levels, decreasing Ab production, removing Abs.
Systemic lupus erythematosus
SLE, lupus
while-body autoimmune disease.
results from Abs against common cellular components (DNA, histones, platelets ++), leading to Type III Hypersensitivity with immune complexes blocking blood vessels, and ultimately progressive organ failiure.
Multiple sclerosis
a neurologic autoimmune siease caused by autoreactive T cells that rec components of the CNS, leading to the desrtuction of the myelin sheath surrounding nerves and progressive neurological dysfunction.
Rheumatoid arthritis
systemic autoimmune disease that usually develops later in life, caused by Abs against cotrullinated protein Ags ant the Fc resion og IgG (called the rheumatoid factor), leading to immune complex deposition in joints and progressive joint destruction via complement.
Defects in AIRE and FoxP3 genes can lead to systemic syndromes (APS-1 and IPEX, respectively) affecting a myriad of Ags, manifesting both autoimmune and immune deficiency-like symptoms, all due to disruption to Treg cells.
Potential causes for autoimmunity (genetic, envorinmental, certains T helper cell types)
Genetic: genetic variants of one or more immune-related genes are associated with predisposition to most autoimmune diseases, most notably certain MHC alleles and immune-regulatory genes (e.g., AIRE and FoxP3).
Enviromental: Envorinmental factors, like diet, obesity, smoking, infection, and mucosal microflora, all have been associated with risk of autoimmune diseases, typically if the individual already are susceptible genetically.
T helper cells: TH17 cells, along with the cytokines they produce (IL-17 and IL-23), are linked to several autoimmune diseases in animal models and humans.
Treatments for autoimmune diseases (list)
3 main strategies:
1) broad-spectrum immunosupressive treatmens
2) immunosupression directed at specific cells or pathways
3) targeted immunotherapy aimed at guiding the host immune cells toward a new and more beneficial pathway
Broad-spectrum immunotherapies
broad-spectrum immune suoressants.
Not cures, just relief from symptoms, providing the patient with acceptible quality of life
examples: corticosteroids and methotrexate.
supress lymphocytes indiscriminantly, inhibiting their survival and proliferation, or by killing those who rapidly divide.
side effects: general cytotoxicity, increased risk of uncontrolled infection, increased risk of cancer.
Immunosupression targeted at specific cell types
if Abs and/or immune complexes are heavily involved in autoimmune pathology, strategies aimed at killing or blocking B cells can improve symptoms. However, in most cases T cells also need to be targeted, as they are the cells that are either directly pathogenic or provide help for autoreactive B cells.
Attempts have been made of targeting CD3 and CD4 on T cells, but with little efficacy. The transfer of Tregs can inhibit diease in mouse models
Therapies that block specific steps in the inflammatory process of autoimmunity
depending on the relevant cell type or cytokine, therapies that block B cells, T cells, specific pathways, and subsets of cells or their products have shown some promise in the treatment of specific autoimmune diseases.
Blocking costimulation as a treatment for autoimmunity
A CTLA-4Ig fusion protein (CTLA-4 + IgG1) is designed to block CD80/86 on APCs from engaging with CD28 on T cells, inhibiting costimulation.
Limited success with MS and IBD, low success in lupus.
Ag-specific immunotherapy
Treatment for autoimmune disease that induces tolerance for the auto-Ags in question and/or redirects the damaging effector response away from its target without impacting other immune processes would be ideal, but it is still in its investigational stages.
Different types of transplants
Autograft: self-tissue transferred from one body site to another in the same individuals
Isograft: tissue transferred between genetically identical individuals, as with identical twins or an inbred strain of mice, when the donor and recipient are syngenetic.
Allograft: Tissue transferred between genetically differnt members of the same species. This is the most common type of tissue graft, ocurring between nonidentical humans or different strains of mice.
Xenograft: tissue transferred between different species.
Auto- and isografts are usually accepted (due to genetic identity)
Tissues that share sufficient antigenic similarity to allow transfer without rejection are histocompatible.
Three important pre-transplantation tests
1) Blood-group matching.
the first human kidney transplant failed due to differnt blood types in donor and recipient.
2) MHC matching (aka tissue typing)
MHC compatibility. If MHC is very important, usually family members (siblings/parents) are the donors. Most rigous MHC testing is conducted in bone marrow translplant, where at least partial HLA matching is crucial to ensure that grafted immune cells like APCs and T cells will be able to rec MHC alleles in the new host.
tissue typing = the serologic or molecular tests that determine HLA compatibility.
If MHC alleles are identical, minor histocompability locus must also be compatible, otherwise the result can be rejection. Therefore, some levels of immunosuppression is usually still needed even if the HLA-identical matches.
3) cross-matching
the presence of any preformed Abs against potential donor alloantigens (present in some but not all individuals in a species) can fuck up a transplant. previos reception of blood or grafts may cause them. Positive cross-matching = bad.
Types of graft rejection
hyperacute
acute rejection
chronic
Hyperactute graft rejection
wihtin hours, caused by damage of the transplanted capillaries by preformed Abs recognizing foreign Ags, including those from ABO and HLA.
Steps:
1) Pre-existing host Abs are carried to kidney graft
2) Abs bind to Ags of renal capillaries ad activate complement
3) Complement split products attract neutrophils, which release lytic enzymes
4) Neutrophil lytic enzymes destroy endothelial cells; platelets adhere to injured tissue, causing vascular blockage
acute graft rejection
induced by T cells (esp CD4+), APCs, and their cytokines after an initial sensitization to donor alloantigens via either direct or indirect presentation to host T cells, leading to inflammation and cell death, usually weeks or months after transplantation.
2 stages: sensitization phase and effector phase.
1) sensitization phase: CD4+ and CD8+ T cells rec alloantigens expressed on the foreign graft, proliferate in response. both minor and major histocompatibility alloantigens can be recognized.
The response to MHC Ags can involve recipient T cells recognizing donor MHC molecules expressed on the surface of cells in the transplant (direct presentation), or recognize processed peptides from donor HLA proteins via self-MHC (indirect presentation).
2) effector phase
hallmark: large influx of leukocytes (esp CD4+ and macrophages)
leukocytes, cytokines (IL-2, IFN-y), APCs
