Immunology Exam 3

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pemphigus vulgaris

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autoimmune, intraepithelial blisterign disease that occurs when IgG autoantibodies against kerotinocytes bind to desmosome cell surface molecules of keratinocytes (particularly desmoglein 1 and 3) resulting in the loss of cell to cell adhesion creating the blisters

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lyymphopoeisis

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production of lymphocytes
depends on rearrangement of B and T cell receptors
positive and negative selection

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positive selection

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occurs in bone marrow or thymus
weak signal through TCR responding to self antigen presented by MHC
this peptide complex signals survival and continued maturation of lymphocyte

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negative selection

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strong binding of MHC to self antigen leads to the self peptide complex signaling apoptosis in the TCR
if lymphocyte does not receive any signals through receptor, cell will also undergo apoptosis

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central tolerance

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positive and negative selection help differentiate cells that are good and can react normally from those cells that are unresponsive or over-responsive
occurs before lymphocytes are released into periphery

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B Cell Development

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stromal cells in the bone marrow support lymphocyte maturation, rearrangement of variable chains of BCR occur or maturation stops and cell dies (heavy chain is rearranged first), receptors allow influence of IL-7, CXCL-12 to regulate development

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chain rearrangement - how do you test if heavy chain is functional

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D-J combination first
V-DJ combination second
temporary light (alpha) chain is used to test heavy (beta) chain
receptor is not complete without kappa or lambda chain

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B cell development continued

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after VDJ rearrangement, B cells express IgM on surface
IgM is capable of binding antigen and is tested against self antigen before being released to peripheral lymph organs. if it cannot bind self antigen or binds to strongly, it dies by apoptosis. however, B cell will try to edit receptor first before giving up and dying.
B cells that have no self-reactivity are moved to periphery and wait for foreign antigen contact. they display IgM and IgD

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receptor editing

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if B cell is strongly self reactive because of strong cross linking of IgM, cell will try to find a functional receptor through editing. this is possible because RAG is still being expressed and continues to be expressed until cell makes functional receptor or dies. receptor will try maternal alleles, then paternal to create a working rearrangement.

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anergy in B cell development

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if the self antigen is soluble and cross links with B cell receptor result in non-reactive B-cells that cannot be stimulated by any antigen even with T-cell help.
have minimal IgM expression and become anergic and are rapidly lost

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clonal ignorance in B Cell development

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b cells that have low affinity for self antigen or do not react to self antigen because the antigen was sequestered can be potentially self-reactive and become pathogenic under certain circumstances leading to autoimmunity.

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B Cell receptor Engagement

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after recognizing foreign antigen in combination with T cell signala (CD40L) and cytokines, cell undergoes another round of DNA rearrangement.
-connecting functinal VDJ unit to conatant region (A, D, E, G, M). done by repeating bases or switch regions between C region genes (class switching)

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class switching

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The ability of B cells to rearrange constant region with variable region allows antibody to have a specific effector function. regulated by cytokines. affinity maturation occurs after class switching
-IgM is first ab produced and good fro agglutination of antigen
-IgG is small and able to diffuse into tissues. good opsonin
-IgE binds to mast cells trigerring release of histamine (allergies)

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avidity and affinity

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affinity describes binding strength of ab to specific given epitope or hapten
avidity describes overall binding strength between ab and antigen

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T Cell develp[ment and Survival

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t cells arise from bine marrow and migrate and mature in thymus
95% of T cells do not complete maturation
stromal cells begin by supporting T Cell growth
-most important are cortical epithelial cells and dendritic cells in junction of cortex and medulla

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TC dev and survival continued (receptor rearrangement)

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pro-T cells will first rearrange beta chain of TCR
-DJ then V-DJ
Then beta chain will associate with invariant alpha chain (like in B cells) and then a zeta chain to form pre-TCR
Signaling through pre-TCR ends beta chain rearrangement and cell now proliferates
then alpha chains rearrange and starts to express both CD4 and CD8
-cell is now double positive

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TCR rearrangement continued

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Double positive cell undergoes positive selection so that it can receive signals necessary for survival
these signals are sent by thymic epithelial cells in cortex that express MHC thus educating Tcells to recognize MHC.
-MHC-I allows only CD8 cells to mature
-MHC-II allows only CD4 cells to survive
Once selected, RAG-1 and RAG-2 are down regulated which stops alpha chain rearrangement

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Self vs. Non-self

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body indirectly identifies self peptides by several mechanisms
-central tolerance via deleting and anergizing self-reactive cells
-high and constant antigen levels indicate self
-presentation of antigen without co-stimulation results in inactivation of cell
-MHc restriction

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Autoimmune disease???

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direct proof someone has autoimmune disease by transferring causative ab or lymphocyte to recreate disease in host
indirect by identifying antigen and isolating it in animal models
circumstantial by familial tendencies, mhc association, improvement with immunosuppressive agents, and lymphocyte infiltrates

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environmental susceptibility (infectious)

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releasing sequestered antigens
-autoimmune myocarditis folling MI
molecular mimicry
-similar structure to another antigen
polyclonal activation
-superantigens can activate large numbers of B/T Cells regardless of antigen specificity by binding to V beta gene domains outside of antigen binding region

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environmental susceptibility (non-infectious)

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hormones and gender differences
drugs that change t cell receptor epitopes
loss of supressor t cells

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Fetal Tolerance

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introduction of different apc bearing another MHC type than self can allow tolerance to new MHC
new MHC on Apc participates in negative selection and is not viewed as foreign
developing lymphocytes become tolerant to new MHC

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initiation of autoimmune response

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believed to start with activation of reactive lymphocytes by self antigens, possibly in context of noncommitant inflammation. these autoreactive lymphocytes then enlist all components of a a full fledged immune response.

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mechanism for tolerance

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anergy
receptor editing
deletion
clonal ignorance
fas-fas L-T and anergized Bcells
regulatory/suppressor t cells
oral tolerance mediated by t cells
low dose tolerance

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epitope spreading

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once autoreactive lymphocytes become established and initiate an autoimmune attack, neutrophils are recruited, complement pathways activated which further exposes other self antigens and recognized by autoreactive lymphocytes. results in expansion of the original disease process

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experimental autoimmune encephalitis

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mouse model of multiple sclerosis
injection of spinal cord homogenate with complete Freund's adjuvant will produce MS symptoms
starts with lymphocytes directed against myelin basic proteins and spreads to other epitopes as well