Tolerance and Autoimmunity Flashcards
AutoImmunity results from the Breakdown of?
Self Tolerance
What induces Central tolerance and in what location?
Immature Self reactive Lymphocytes in Primary Lymphoid Organs
What induces Peripheral tolerance and in what location
Induced by mature self reactive lymphocytes in Lymph nodes or peripheral sites such as submucosal tissues
Three mechanisms to deal with recognition of self antigen in the central tolerance
Deletion by Apoptosis
Change of BCR specifitity
development of Treg cells
Three mechanisms induced in peripheral tolerance to deal with Mature self reactive lymphocytes
Inactivated (anergy)
Deleted ( apoptosis)
Suppressed by the Treg cells
Central T cell Tolerance location and Process
In Thymus
Strong binding to self Ags get deleted
No affinity at all undergo apoptosis
binding self antigen under certain threshold the develop into effector T cell
Small percentage develop into Treg Cells
Treg Cells
Develop in the Thymus
Positively selected due to strong TCR interactions with self AG
Not eliminated because can produce Anti Apoptotic molecules to protect them
Express FOXP3 and CD4+ and CD25+
Tregs need what to survive and function
IL-2
Induced Treg Cells
Produced outside of the Thymus and is induced by FOXP3 in Naive CD4+ upon AG recognition in the presence of TGF-B
Ag recognition in the presence of TGF-B and IL-6
Creation of Th17 cells rather than iTreg because IL-6 represses FoxP3 and induces expression of REtinoic acid receptor related orphan nuclear receptor (RORyt) to make Th17
Where are Inducible Treg cells produced
in the periphery especially in GI tract and Lymph nodes
What cytokines do Treg cells release
IL-4, IL-10, TGF-B
3 mechanisms of Peripheral tolerance?
Anergy- functional unresponsiveness
Suppression: Block activation of effector cell
Deletion: Promote APoptosis
what is the mechanism of T cell Anergy
Ag recognition with out adequate CD80:CD28 costimulation binding
What is the mechanism of T cell suppression
T rells may engage inhibitory receptors: CTLA-4 and PD-1
expressed on both CD4 and CD8
Therapeutic application of Anti-CTLA-4 and anti-PD1
Treat patients with cancer to enhance antitumor immune response leading to breakdown of tumor but does ldevelop auto immune reactions
What is the intrinsic pathway of apoptosis
Mitochondrial release of cytochrome C that activates caspase 9 that induces Death pathway
What is the Extrinsic pathway of Apoptosis
Death receptor FasL and Fas or TNF receptor that initiats Caspase 8 to induce apoptosis
3 outcomes of B cell Tolerance
die by apoptosis of high affinity for self
Receptor editing
Low avidity my lead to anergy in the bone marrow
BCR editing
the rearrangement occurs on the k light chain.
All BCR that contain the lambda light chain underwent BCR editing
Peripheral B cell Tolerance and mechanism of?
Mature B cell that recognize self Ag in peripheral tissues in the absence of specific Th cells may be rendered funcutionally unresponsive or die by apoptosis
CD22 inhibitory receptor is phosphorylation by Lyn and recruits SHP-1 tyrosine phosphatase to attenuate the BCR signaling
What are some ways Treg cells mediate the peripheral tolerance
inhibit CD4 T cell activation by APCs
inhibit T cell differentiation into CD8 CTLs
Prevent T cells from providing help to B cells in producing Abs
what is the function of Symbiotic bacteria
inhibit pathogen colonization of the GI tract and skin and have anti inflammatory activities
How do Microflora suppress pathogens
induction of regulatory immune resposes involving Treg cells and IL-10
What do Gut microbiota have an important role in the development of?
Gut associated Lymphoid tissue (GALT)
How do You break Central Tolerance
Breakdown of AIRE
Autoimmune Polyendocrine syndrome (APS)
destruction of endocrine organs
What Cells play an important role in negative selection of the Central Tolerance
Thymic Epithelial Cells function as APCs
THymic Epthelial Cells
Have AIRE which is an important protein that helps express the peripheral tissues restrected Self (TRAs) that are presented to developing T cells
What happens in the absence or mutation of AIRE
No expression of tissue restricted Ags (TRA) therefore no negative checking of immature T cells that lead to non elimination of self reactive T cells
Breaking of Peripheral Tolerance: C4
SLE, cant clear the Immune complexes that leads to accumulation in blood and tissues
Breaking of Peripheral Tolerance: CTLA-4
Failure of Anergy and suppression of CD4 T cells,
Polymorpismim diseases: Type 1 diabetes and Graves Disease
Breaking of Peripheral Tolerance: Fas/FasL
Cant induce Apoptosis and lead to non dying self reactive B and T cells
ALPS
Breaking of Peripheral Tolerance: FoxP3
Deficiency deficiency in T cells
Breaking of Peripheral Tolerance: IL-2 or IL2Ra/b
Defective development and survival or function of regulatory T cells
Breaking of Peripheral Tolerance:SHP-1
Failure of negative regulation of B cells
Clearance of Immune Pathways
Need erythrocytes to bind to C3b (complement) on Immune complexes using its CR1 receptor
Role of CTLA-4
is a homolog to CD28 and acts as an inhibitory receptor that binds CD80/B7) on B cells to terminate response
Two important properties of the CTLA-4 receptor
low expression on resting T cells until cells are activated by Ag
Once expressed, CTLA-4 terminates continuing activation of these responding T cells
Intrinsic function of CTLA-4
Engagement of CTLA-4 on a T cell that eliminates furthur activation
Extrinsic function of CTLA-4
CTLA-4 on T regs bind B7 molecules on APC to block available B7 receptors for CD28
How auto Immunity is prevented: immunological ignorance
Physical Separation
BBB Eye pregnant uterus ovary testis Adrenal Cortex Hair follicles
How auto Immunity is prevented: Deletion
use FasL to promote Apoptosis
How auto Immunity is prevented: Inhibition
Utilizing CTLA-4
How auto Immunity is prevented: Suppresion
Use of Treg cells
Various Types of Auto immune diseases and what genes are they predominantly found in
Class II HLA alleles (DR, DQ)
Ankylosing spondylitis
Rheumatoid Arthritis
Type 1 Diabetes
Pemphigus Vulgaris
Microbial Ags can Initiate and Autoimmune disorder: Molecular mimicry
Cross reactivity effect cardiac myosin in rheumatic fever caused by streptococcal infection
Multiple sclerosis, T cells affect Mylein basic protein via Epstein Barr virus, influenza or human papillomavirus
Microbial Ags can Initiate and Autoimmune disorder: Poly clonal bystander activation
Robust inflammatory response lead to activation of auto reactive lymphocytes in the cytokine field
Microbial Ags can Initiate and Autoimmune disorder: Release of previously sequestered Ags
Microbes kill cells releasing sequestered Ags (DAMPS) that lead to immune response
Inflammatory bowl syndrome
Changes in Gut microbiota lead to an inflammation response that can harm the Gut
Systematic Lupus Erythematosus
Type 111 hypersensitivity
rash, arthritis, glomerulonephritis, and vasculitis due to Immune complex build up
Starts by defective clearance of apoptosis (UV damage)
Rheumatoid ARTHIRITIS (RA)
inflammatory of the small and large joints
inflammation of the synovium with destruction of bone and cartilage
Type 4 hypersensitivity (Th17 play a role)
circulating IgG and IgM called rheumatoid factor
