Glossary of IHR Test 2 Flashcards
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- Name 3 characteristics of T cells.
- 1) type of lymphocyte that protects from foreign antigens
2) acticates other cells of immune system with TCR on surface
3) only sees fragments of foreign peptide that are presented by MHC
- Major Histocompatibility Complex
What is it?
Is it polymorphic?
- - gene locus that encodes molecules important in immune recognition and singaling b/w cells of immune system
- highly polymorphic (many variations/alleles)
- What is the function of MHC?
- the physiologic function of MHC miolecules is to present peptides to T cells
- Class 1 MHC present intracellular antigens to ____ ________.
- CD8+ cytotoxic T cells
- unit that the set of MHC alleles present on each chromosome is inherited as
- Class II MHC present extracellular antigens to __________________.
- CD4+ helper T cells.
- syngeneic vs. allogeneic
- syngeneic: every member of the species has identical gene (homozygous at that loci)
allogenic: different members/strains may express different alleles
- linkage disequilibrium
- association of certain HLA alleles at different loci more frequently than would be predicted by random assortment
- True or False: Human MHC molecules are called human leukocyte antigens (HLA).
- name the four domains of MHC molecules
- 1) extracellular peptide-binding cleft
2) immunoglobulin-like region
3) transmembrane region
4) cytoplasmic region.
- Where is the human MHC complex mapped?
- short arm of chromosome 6
- Which domain contains binding molecules for T-cells CD4 and CD8?
- the immunoglobulin-like region
- MHC Class 1 has which HLAs?
- HLA-A (over 40 alleles)
HLA-B (over 100 alleles)
HLA-C (over 10 alleles)
- cytosolic protease complex that degrades cytosolic proteins into peptides that are presented by class I molecules.
- MHC Class II has which HLAs?
- HLA-DR (about 30 alleles)
HLA-DQ (~9 alleles)
HLA-DP (~6 alleles)
- tissue typing
- technique used to determine the MHC alleles expressed on an individual’s cells. Typing is performed by adding the cells to be tested (usually lymphocytes) to antisera of defined HLA specificity. Addition of complement kills the cells and this can be visualized by staining with a dye that is taken up by dead cells. Cell death indicates that the test cell carried the allele in question.
- MHC molecules are ___________ expressed, which maximizes _________________.
- MHC molecules are codominantly expressed, which maximizes the number of MHC molecules available to bind peptides to present to T cells.
- cytotoxic antibody screening
- tissue typing also called lymphocytotoxicity testing can be used to detect anti-HLA antibodies in serum by testing the serum against a panel of lymphocytes with known HLA types.
- mixed lymphocyte reaction (MLR)
- an in vitro assay for T cell recognition of allogeneic MHC molecules and is based on the fact that T lymphocytes are stimulated to grow in the presence of cells expressing allogeneic class II molecules.
- Compare polypeptide chains of Class 1 MHC to Class II MHC polypeptide chains.
- Class 1 MHC - α (heavy chain) and β2 microglobulin (from chromosome 15 - non-MHC)
Class II MHC - α and β
- Compare locations of polymorphic residues for Class 1 and Class II MHC complexes.
- Class 1 - α1 and β2 domains
CLass 2 - α1 and β1 domains
- Where is the binding site for the T cell co-receptor?
- Class 1 - α3 region binds CD8 (conserved among all class 1)
Class 2 - β2 binds CD4
- What size peptide can Class 1 and Class 2 MHC bind?
- Class 1 - peptides of 8-11 residues
Class 2 - peptides of 10-30 residues or more
- The full assembled MHC molecule (both class 1 and class 2) is a heterotrimer consisting of the following three parts:
- 1) α chain
2) β2 microglobulin (Class I),
β (Class II)
3) bound antigenic peptide
- How many class 1 and class 2 molecules are inhereted from each parent? Which class expresses heterologous pairing?
- 6 class I/II molecules are inhereted - 3 alleles from each parent. Class II has heterologous pairing, meaning there can be 10-20 Class II molecules present in a heterozygote (more then the 6 Class I molecules present).
- Which molecules have broad specificity for peptide binding, and which receptors have fine specificity?
- MHC molecules have broad specificity for peptide binding, whereas the fine specificity for Ag recognition is in the T cell Ag receptors.
- Which cells express Class I MHC?
Which cells express Class II MHC?
- Class I molecules are expressed constituitively on virtually all nucleated cells.
Class II recognize antigen presenting cells (ex. dendritic cells, B cell)
- Name 5 cytokines that can upregulate the expression of Class 1 molecules.
- 1) IFN-α
5) LT (lymphotoxin)
- Name some upregulators of Class II MHC molecules.
- IFN-γ produced by NK cells can upregulate Class II in innate immune response. IFN-γ produced by antigen activated T cells can upregulate class II in adaptive immune response.
TNF can upregulate Class II MHC in dendritic cells.
B cells constitutively express Class II, but can increase expression under IL-4.
Nonimmune cells can express Class II under high levels of IFN-γ.
- Allorecognition only occurs in three situations:
- 1) transplantation
2) blood transfusion
- Which disease is associated with HLA allele B27?
- There is a 90-100% relative risk of alkylosing spondolysis if you have HLA allele B27.
- Which HLA alleles have a major effect on graft survival?
- HLA-B and HLA-DR
- True or False: B cells are specific for conformational determinants of an antigen and therefore distinguish between native and denatured antigens.
- T cells recognize ________ epitopes, allowing them to respond to both native and denatured protein.
- Dendritic Cells
- Precursors found in peripheral blood and mature cells in secondary lymphoid tissue (spleen, lymph node, mucosal lymphoid tissue). Most efficient APCs for initiating immune response in naive T cells because of high levels of MHC class II and co-stimulatory molecules.
- APC found in all types of tissue, present to effector T cells leading to effector T cell activation, and lead to cell mediated immunity (additional macrophage activation) and death of the microbe.
- B cells
- B cell activation and antibody production leads to humoral immunity. B cells use Ig on surface to bind to Ag and internalize it. In secondary immune response, a low conc of Ag can expand specific B cells, leading to effective protection.
- Name 4 differences between immature and mature dendritic cells.
- 1) Principal function: immature cells - antigen capture; mature cells - antigen presentation to T cells 2) Immature cells express Fc and mannose receptors; mature cells do not 3) Mature cells express molecules involved in T cell activation (B7, ICAM-1, IL-12); immature cells do not
4) the half life of MHC Class II is greater then 100 hr for mature cells; it is about 10 hrs for immature cells
- True of False: APC must express MHC molecules that the T cell recognizes as self in order for the T cell to recognize and respond to a foreign protein antigen presented by the APC.
- True. This is the phenomenon of MHC restriction.
- What prevents peptides meant for binding to Class I from binding to Class II?
- Invarient chain, then CLIP part of invarient chain, bind to antigen-binding part of Class II to prevent other peptides from binding.
- Which epitopes bind most avidly to MHC?
- immunodominant epitopes - T cells respond to the immunodominant epitopes of antigens.
- Which cells can cross-present antigen?
- Dendritic cells have the unique ability to present using either MHC Class I or MHC Class II.
- True or False: CD1 is a non-polymorphic MHC-like molecule.
- True. CD1 associates with beta-2 microglobulin and can present mycolic acid and liparbinomannan from mycobacteria to T cells.
- Lympocyte Maturation
- process by which bone marrow-derived lympohocyte progenitors develop into mature lymphocytes that populate peripheral lymphoid tissue.
- Lymphocyte Repertoire
- total number of T cell specificities for different antigens in an individual.
- What is the major site of T cell maturation?
- Which interleukin stimulates early T cell maturation?
- What causes X-linked severe combined immunodeficiency disease in humans?
- Mutations in the IL-7 receptor Ƴ chain. Disease is characterized by a block in T cell development.
- somatic recombination
- process in which a set of germline DNA sequences that are initially separated from one another are brought together by enzymatic deletion of intervening DNA
- positive selection
- process that eliminates immature T cell that do not recognize self MHC or recognize self MHC with high avidity. Positive selection insures maturation of T cells that bind weakly to self-MHC molecules.
- negative selection
- process that eliminates developing lymphocytes whose antigen receptors bind strongly to self antigens.
- Which type of selection takes care of inadequate or too much recognition of MHC? Which type of selection takes care of too much binding to self-antigens?
- Positive selection - MHC
Negative selection - antigen
- True or false: Genes encoding the TCR α, β, and γ chains are in three separate loci whereas the TCR δ chain locus is found within the TCR α locus.
- Each germline TCR locus includes _, __ and __ gene segments tna the TCR β and δ loci also have ___ segments.
- Each germline TCR locus includes V , J and C gene segments tna the TCR β and δ loci also have D segments.
- At the 5' end, there is a cluster of several __ gene segments, and at varying distances 3' of the __ genes are the __ gene segments.
- At the 5' end, there is a cluster of several V gene segments, and at varying distances 3' of the V genes are the C gene segments.
- immature, developing lymphocyte in the thymus
- Where are immature thymocytes found? Where are mature T cells found?
- immature thymocyte - cortex
mature T cells - medulla
- What are tbe four possible phenotypes for a thymocyte?
- 1) CD4- and CD8-
2) CD4+ and CD8+ (majority)
- Expression of _______, _____, and ______ occurs prior to the start of any selection.
- Expression of TCR αβ, CD4, and CD8 occurs prior to the start of any selection.
- Positive selection of T cells requres the recognition of self MHC molecules in the thymus by the TCRs of thymocytes with the following phenotype:
- double positive - CD4+ and CD8-
- Thymocytes with class I restricted TCRs become:
- CD8+ CD4-
- Thymocytes with class II restricted TCRS become:
- CD4+ CD8-
- Peptides bound to MHC molecules on thymic epithelial cells play an essential role in _________ selection.
- Bone marrow-derived dendritic cells are important in _________ selection.
- Stage of T cell activation where antigen is presented to teh CD4 T cell by APC in the presence of co-stimulating signal. What is the co-stimulating signal?
- Recognition Phase. B7-1 or CD80 and B7-2 or CD86 are co-stimulatory molecules present on the APC while CD28 is a co-stimulatory molecule prsent on the T cells.
- Phase during which the production of autocrine growth factors such as IL-2 lead to proliferation and differentiation.
- Activation Phase. When IL-2 binds to IL-2 receptor, cells move from G1 to S phase.
- In this phase, T-cells dramatically expand in response to IL-2 and other cytokines.
- Clonal expansion/differentiation
- Phase in which T-cells carry out their functions. What are their functions?
- Effector phase.
CD4 - produce cytokines that lead to B cell activation for antibody production, macrophage activation, and help for CTL.
CD8 - kill antigen bearing cells, produce cytokines.
- When is the critical period for clonal expansion?
- 4-10 days after antigen is presented to naive T cell - during the activation phase.
- Name the two competance singals required to activate T cells.
- 1) Ag-MHC interaction with TCR.
2) Co stimulatory factors B7-1 or CD80 and B7-2 or CD86 prsent on the APC and CD 28 present on the T-cells.
- True or False: Cross linking of receptors (Multi-chain immune recognition receptors - MIRRs) is required to transduce signals.
- True. The MIRRs (TCR< BCR, FcR) have an extracellular domain (where Ag or Fc bind) and an intracellular domain.
- Which cytosolic components of the T cell receptor transduce signal?
- ITAMs - immunoreceptor tyrosine-based activation motif
- turn off the cell
- Does an activated T cell require costimulation?
- Name 3 ways in which the primary and secondary antibody responses differ.
- 1) time lag after antigen exposure
2) antibody isotype and affinity
3) amount of antibody produced
- The BCR is a multimeric complex based on surface Ig and a heterodimer of _____ and ______.
- Ig-α and Ig-β -- both are transmembrane proteins which are required for signaling.
- germinal centers
- site of antigen driven hypermutation, affinity maturation and selsection
(activated B cells migrate to teh follicles and form germinal centers)
- Name two cells that are in germinal centers.
- 1) activated B cells
2) follicular dendritic cells that trap antigen and are potent stimulators of previously activated B cells
- True or False: B cells activated by helper T cells singal (CD40L and cytokines) undergo isotype switching adn each isotype has distinct effector functions.
- What is the first isotype to be produced?
- IgM - it is produced from birth.
- IL-4 induces ___ isotype switching.
TGF-beta increases ____ production.
IFN-gamma enhances _____.
- IL-4 induces IgE isotype switching.
TGF-beta increases IgA production.
IFN-gamma enhances IgG2A.
- Which B cells will be rescued from death in the germinal center?
- Only B cells with highest affinity for antigen will be rescued from cell death in the germinal center.
- B cell antigen receptor complex
- plays role in helpter T cell-B cell interaction, binds to CD-40 ligand
- marker of subset of B cells, fetal B cells
- costimulator for T cell activation and binds to CD28 and CTLA-4 on T cells. B7-1 is called CD80.
- CR2 (CD21)
- complement receptor for C3d and EBV
- CR1 (CD35)
- C3b receptor
- FcϒR11 Fc receptor, involved in negative feedback control
- present in all B cells, reduced in plasma cells
- Hyper IgM disease is due to..
- Hyper IgM disease is due to mutated CD40 ligand on T cells which prevents CD40 on B cells from interacting with T cells.
- mucosal immunity
- major class of antibody is IgA
involves the GI and respiratory tracts
IgA is produced by plasma cells in the lamina propia of mucosal tissue
- Primary immunodeficiency disease
- The immune deficiency itself is the cause of the disease.
These are genetic disorders that usually - but not always - appear early in infancy or childhood. The databases show that while the effect at the protein level may be the same from patient to patient, the specific genetic defect can vary enormously.
- Secondary immunodeficiency disease
- The deficiency is a result of some other process. Examples include malnutrition, cancer, immunosuppressive drugs, or infection with HIV.
- SCIDs - what are they?
- genetically heterogeneous group of diseases in which the development and/or function of both T and B cells is profoundly impaired.
- SCIDs - symptoms?
- SCIDs usually present in infancy with variable combinations of the following: failture to thrive, oral and/or cutaneous candidiasis, chronic diarrhea, and opporunistic infections as well as other types of infections.
- X-linked recessive SCID
- Few, if any, T cells in circulation. Normal B cell levels, but B cells have severe hypogammglobulinemia because there is no help recieved for antibody production. Most X-linked SCID cases are due to mutations encoding the ƴ chain. IL-7, therefore, cannot exert its normal effect.
- autosomal recessive SCID
- results from enzyme deficiencies lack of adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP). Few T cells or B cells, severe hypogammaglobulinemia. Enzyme deficiencies lead to a buildup of toxic products within lymphocytes.
- Mutation in RAG genes - SCID
- mutation in RAG genes lead to a defect inantigen receptor gene recombination and result in the absense of mature B and T cells.
- Bruton's agammaglobulinemia (X-linked agammaglobulinemia or XLA)
- Defect in gene on the long arm of the X chromosome, which encodes for a cytoplasmic tyrosine kinase (also known as B cell tyrosine kinase or Bruton's tyrosine kinase or BTK). This gene is required for transducing singals that are required for B cell maturation.
If someone has this disease, pre-B cells are present in teh bone marrow but there is no further B cell differentiation. There is also an absense of all classes of Igs.
- Cause of DiGeorge Syndrome?
(congenital thymic aplasia)
- DiGeorge Syndrome is caused by deletion in chromosome 22q11.2 Patients are susceptible to mycobacterial, viral, and fungal infections.
- Name 4 symptoms of DiGeorge Syndrome.
- (1) Absense of the thymus due to filure of the development of the 3rd and 4th pharyngeal pouches during gestation.
(2) Hypoparathyroidism - abnormal calcium homeostasis and muscle twitching.
(3) Cardiovascular anomalies.
(4) Abnormal faces - defects in the ears, mouth, jaw, and eyes.
- X-linked hyper-IgM syndrome
- results from defective switching of B cells to the IgG and IgA isotypes with a compensatory increase in IgM. This genetic defect results in mutations in the gene encoding CD40 ligand.
- Common variable hypogammaglobulinemia (CVID)
- diagnosis made once all other syndromes have been excluded. B cell counts can be normal but the cells mature into antibody-secreting cells. T cell numbers are normal.
- Name 3 defects in T cell activation and function.
- 1) Mutations in CD3 ε or ϊ genes
2) Mutation in ZAP-70 gene
3) Reduced synthesis of cytokines (e.g. IL-2 and IFN-ϊ)
- Bare Lymphocyte Syndrome
- defective MHC class II expression patients express little or no HLA-DP, HLA-DQ, or HLA-DR on APCs and fail to express MHC class II in response to IFN-ϊ. Deficient DTH responses and antibody responses to T-dependent antigens.
- Defective MHC Class I expression
- Decreased CD8+ T cells. In some cases there is a defect in the gene that encodes TAP that delivers peptides to the ER so that they can bind to MHC Class I for presentation. Patients generally have respiratory tract bacterial infections rather than viral infections that would have been expected.
- Wiskott-Aldrich syndrome (WAS)
- characterized by eczema, thrombocytopenia, and bacterial infections. Defective gene is supposed to encode a cytosolic protein that plays important roles in signal transduction and the regulation of cytoskeleton in lymphocytes.
- Ataxia telangiectasia
- charaterized by cerebellar ataxia, oculocutaneous telangiectasias, a variety of immune deficits, radiation sensitivity, and a high incidence of lymphoma. γδ T cells are about 50% of the total number of peripheral lymphocytes whereas in normal individuals they are about 1-5%.
- IgA deficiency
- Defect in maturation process that leads to release of synthesized IgA. Defect may be in B cell itself or at level of T cell helper but the result is a virtual absence of serum and secretory IgA. Some individuals with this have infections of the respiratory, gastrointestinal and urogenital systems.
- Transient hypogammaglobulinemia of infancy
- delay in maturation of immune response. Kids have unusually high number of infections; few have serious invasive bacterial diseases. Generally, the immune system becomes normal by about age 2.
- What is the normal number of respiratory infections per year for kids?
- Chronic granulaomatous disease (CGD)
- Defective production of NADPH oxidase - superoxide anions and hydrogen peroxide cannot be formed and ingested microorganisms cannot be killed.
- How is the diagnosis for CGD made?
- Diagnosis is made by the inability of phagocytes to reduce nitroblue tetrazolium (NBT) dye after a stimulus. IFN-Ύ therapy is now commonly used for the treatment of X-linked GCD.
- Leukocyte adhesion deficiency type 1 (LAD-1)
- defective production of CD18, the β2 integrin subunit. It is normally found on neutrophils, monocytes, and lymphocytes - without it, the cells can't adhere to vascular endothelial cells (which is supposed to prevent extravasation). It's absense also prevents CTLs and NK cells from adhering to target cells as well as preventing T adn B cells from forming conjugates.
- Leukocyte adhesion deficiency type 2 (LAD-2)
- generalized defect in fucose metabolism due to defective production of the leukocyte ligands that are required for binding to endothelial E- and P-selectins. This leads to a failure of leukocyte migration.
- Chediak-Higashi syndrome
- cellular abnormality leading to increased fusion of cytoplasmic granules that affects the lysosomes of neutrophils and macrophages, cells of the nervous system, and platelets. Neutrophils are deficient in microbiocidal activity as well as chemotaxis adn phagocytosis. Macrophages and dendritic cells may have impaired antigen processing and presentation.
- Heriditary angioneurotic edema (HANE)
- most common complement deficiency, C1 inhibitor deficiency, patients with this deficiency have recurrent swelling of various parts of the body - if swelling involves the upper airway, patient may die from obstruction.
- Enterobacteriaceae characteristicss
- non-spore forming gram-negative rods with capsule or slime layer; can be motile or non-motile, have pili for attachment to host cells and other bacteria, are speciated by carbohydrate fermentation tests
- Enterobacteriaceae members can cause
- diarrhea, dysentery, typhoid fever, hemorrhagic colitis, urinary tract infections, septicemia, pneumonia, meningitis
- Enterobacteriaceae antigenic structure (Name 3 parts)
- i. capsular or K antigen - mucopolysaccharide (called Vi antigen in Salmonella)
ii. Somatic or O antigen (cell wall): repeating oligosaccharides, lipopolysaccharide
iii. flagellar or H antigens: protein, especially useful in typing Salmonella typhi
- Name two types of determinants of pathogenicity in enterobacteriaceae.
- i. endotoxin - lipid A portion of lipopolysaccharide is toxic to animals, produces fever, fatal shock
ii. enterotoxin - produced by bacteria, affect small intestines to cause transduction of fluid into intestinal lumen (diarrhea)
- Vibrionaceae characteristics
- non-spore forming halophilic curved rods that are highly motile with a gram-negative cell envelope struture; oxidase-positive
- For which family of enteric bacteria is lipopolysaccharide O antigen important?
- Family Vibrionaceae
- Name 6 characteristics of Enteropathogenic E. coli (EPEC).
- - causes watery diarrhea
- affects newborns and infants <1 yr (spread from adults)
- colonizes rapidly
- cause of septicemia
- cause of dehydration
- major cause of pediatric diarrhea and death in developing nations
Treat with neomycin
- How would you assay/diagnose EPEC?
- PCR for virulence factors
- Name 4 characteristics of Enteroaggregative E. coli (EAggEC).
- - persistant diarrhea in children and infants <6 mths
- non-invasive, heat-labile toxin
- adheres to surfaces of specific cell types - clumping
- treat with rehydration
- How would you assay/diagnose EAggEC?
- tissue culture assyas for aggregated adherence.
- Name 2 characteristicss of diffusely adherent E. coli (DAEC).
- - watery diarrhea in adults and children
- adheres diffusely to surfaces of various cell types
treatment is rehydration
- How would you assay/diagnose diffusely adherent E.coli (DAEC)?
- tissue culture assays for diffuse adherence
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