Immune physiologic D/C Flashcards Preview

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Flashcards in Immune physiologic D/C Deck (53):
1

what cytokines do CD4+ Th1 cells secrete?

TGF beta, interferon gamma, IL-3, IL-10, ?IL-2 absent IL-4 and IL-5.

2

Type I interferon consists of what interferons?

Interferons that stimulate the INF alpha receptors, R1 and R2 and consist of INF alpha, INF beta, and INF Omega (~20 kd). Interferon alpha is coded by 13 genes on chromosome 9, and is strongly produced by plasmacytoid dendritic cells. They are the proximal cause of prostaglandin E2 release, fever, and stimulate the mu receptor causing analgesia.

3

what is LFA-1 (Lymphocyte function-associated antigen 1 )?

Lymphocyte function-associated antigen 1 is a heterodimer integrin CD11a (integrin alpha L, p189) and CD18 (integrin beta-2). This is present on both T and B cells and binds to ICAM-1 (CD54) on antigen presenting cells.

4

What stimulates Th17 cells to produce of IL-17, and what are the consequences ?

Th17 cells are developed from precursor helper T cells by TGF-beta, IL-6, IL-21, and IL-23. Th17 cells are triggered by IL-6, -23, and -1 beta, to produce IL 21, IL-22 and IL-17. IL-17 activates neutrophiles which then turn on NfkB as well as IgM, and IgA B cells

5

What proteins make up the T cell receptor complex?

TCR alpha and beta chains ( 95%) or epsilon and gamma (5%). 3 additional dimeric signaling molecules are associated, 2 types of CD3 (one chain each of CD3E (epsilon), CD3Z (Zeta), CD3D (delta), and CD3G (gamma)), and CD247 (zeta chain dimer).CD3 chains belong to the immunoglobulin superfamily. The transmembrane portion is negatively charged but associates with the positively charged TCR complex. Intracellular portion contains ITAM (immunoreceptor tyrosine-based activation motif) structure, which accounts for downstream T cell signaling.

6

What part of the T-cell receptor complex binds to the antigen in the MHC groove ?

Complementarity determining region 3 (CDR3) on the beta chain. NOT CD3 -cluster of differentiation 3.

7

What is CD4?

CD4, the product of the CD4 gene, is a membrane-bound glycoprotein with 4 immunoglobulin domains, 2 variable and 2 constant. The D1 (variable) domain interacts with the Beta 2 domain of MHC class 2 molecule thus accounting for MHC class 2 restriction.

8

How many binding sites must connect to stimulate T helper cell activation?

2.The beta chain of the T cell receptor must recognize the antigen in the MHC class 2 groove and CD4 must associate with the T cell receptor and bind to the beta-2 domain of the MHC class 2 complex.

9

How strong is the attachment of the T cell receptor to the immunogen on the MHC molecule?

The binding is weak permitting easy on easy off interrogation of multiple receptors. Additional binding such as CD4 and presence of appropriate cytokines determines the T cell response.

10

What is composition of the IL-12 family?

IL-35 is a dimer containing p35 (IL-12 alpha) and EBI3 (Ebstain Bar virus Induced 3) chain that binds to gp130 .
IL-27 is a dimer containing P28 (IL-27)and EBI3.
IL-12 is a dimer containing p35 (IL-12 beta 2) and p40 (IL-12 beta1).
IL-23 is a dimer containing p19(IL-23), and p40 (IL-12 beta 1 ).
The chains associate via Jak and Tyk motifs which phosphorylate STAT 3 and 4 transcription factors.

11

What is the difference between anti-Sm, anti-U1 RNP antibodies and anti ribosomal P protein antibodies

anti-Sm binds Sm proteins (SmB, SmD2…) that have a heptameric ring structure, forming complexes with uridine rich RNAs (U1,2,4,5) in cytoplasm, critical for transport of snRNPs into nucleus for splicing. Specificity for SLE is 55-100%, 10-50% sensitive.
Anti-U1 RNP binds to U1 snRNP complex containing 70-kD,A,or C proteins, found in MCTD and lack specificity for SLE.
Ribosomal P protein is a protein on the 60s ribosomal subunit and antibodies to it are highly specific for SLE.

12

What are regulatory B cells?

Regulatory B cells (Bregs) secrete IL-10 and and TGF-beta.

13

What cytokines are included in the IL-10 superfamily?

IL-10 (CSIF cytokine synthesis inhibitory factor) family includes IL-19, IL-20, IL-24, IL-26, and sometimes IL-28 and IL-29. IL-10 down regulates Th1 responses, MHC class !! expression, and costimulatory molecules on macrophages. It downregulates TNF alpha, interferon, and GM-CSF. It upregulates IL-6 in muscles during exercise.

14

What S100 type protein is involved in psoriatic inflammation?

S100 proteins are calcium binding proteins with 2 helix loop helix binding sites. Unlike calmodulin they are cell type specific. The S100A7 gene codes for psoriasin which is an inflammatory cytokine in autoimmune skin conditions including psoriasis. S-100 proteinIs are found in melanomas, schwamnomas, neurofibromas, histiocytomas, and clear cell sarcomas. They are markers of inflammatory disease and act as an antimicrobial.

15

Arginine can generate citrulline via deimination, which might generate auto antigens from what sources?

Citrulline modified auto antigens include filaggrin, fibrin, vimentin, collagen, and alpha enolase. Filaggrin is a protein in the stratum granulosum of the skin, vimentin is in intermediate filaments, and alpha enolase is a glycolytic enzyme thought to be an auto antigen in Hashimoto's encephalopathy, severe asthma, and Behcet's disease.

16

What are defensins?

Defensins are small cationic proteins with high cystiene content that kill pathogens by forming holes in bacterial and fungal cell membranes.

17

What is the effect of IL-22 (IL-10 related T cell inducible factor)

IL-22 is structurally similar to IL-10, stimulates innate immune responses in epithelial cells, S100 protein production, and defensins, It is produced by dendritic cells and T cells.

18

What are immunophilins?

Immunophilins are highly conserved proteins that bind to immunosuppressive drugs, FKBPs and cyclophilins. FKBP's bind FK506 and cyclophilins bind cyclosporine. FKBP's are peptidyl-prolyl cis/trans isomerase which participate in protein folding, receptor signaling, protein trafficking, transcription, apoptosis, and T cell activation.

19

What are chemokines ?

Chemokines recruit immune cells to sites of infection.They are 8 – 10 kekodaltons sized proteins containing 4 cysteines which determine their 3 dimensional shape. Some are homeostatic and control cells during physiological activity. They are found in all vertebrates, some viruses and bacteria, but not invertebrates.

20

What does TGF-beta do?

TGF-β induces apoptosis through the SMAD and DAXX pathways, regulates the cell cycle through c-myc suppression, and the immune system by blocking activation of lymphocytes and monocyte derived phagocytes.

21

What is the endogenous ligand that forms an inflammasome in response to bacterial and viral DNA?

AIM2 (absent in myeloma 2) is an interferon-inducible protein, 344 aa, which forms part of the inflammasome responding to bacterial and viral DNA.

22

What happens in the SMAD pathway

SMAD (mothers against decapentaplegic- a Drosophila gene, small body size- a worm gene) proteins transduce extracellular signals from TGF-β activating downstream gene transcription.

23

What is the structure of TGF-beta family proteins?

TGF-beta refers to a superfamily of structurally related regulatory proteins. TGF-beta-1 has 22 aa derived from C-terminal proteolytic cleavage. They form disulfide linked homo or heterodimers with intra-chain disulfide bonds. Family members use serine/threonine receptors to activate various's SMAD pathways.

24

What is IL-13?

IL-13 is similar to IL-4 structurally, increases IgE and metalloproteinase production. It induces many features of allergic disease such as airway hyperresponsiveness, mucus hypersecretion, and Schistosoma granuloma formation.

25

What is TRIM5alpha?

TRIM5alpha (TRIpartite Motif containing motif 5) is a 493 aa gene product retrovirus restriction factor found in most primate cells.

26

How does transcription factor T-bet produce interferon?

T-bet from gene TBX21, binds to a T-box promoter producing T-bet which stimulates Th1 and NK cells to produce interferon gamma.

27

what is GATA-3?

GATA-3 is the transcription factor inTh2 cells that stimulates the production of IL-4, IL 13, and IL-8.

28

What type of interferon seems active in rheumatic diseases?

Interferon 1 inducible genes are increased in whole blood in SLE, dermatomyositis, scleroderma and in affected tissues in SLE, dermatomyositis, and rheumatoid synovium.

29

What sort of effectors are stimulated by interferons?

interferon type I (Alpha +8 others-13 subtypes) bind to IFN-alpha/beta receptor and stimulate antiviral innate immune responses, opiate receptors to produce prostaglandins and fever and analgesia, the reduction of growth factors and angiogenesis factors by immune cells. Subtypes vary by cell of origin and species.
Interferon type II binds to INFGR which in humans is INF gamma.
Interferon type III stimulates receptor IL10R2, and is produced and some types of virus infections.
Tetherin ( BST2-bone marrow stromal antigen 2 gene product) produced by interferon stimulation and resides in lipid rafts where it tethers encapsulated viruses to the cell membrane thus preventing viral release.
Viperin is a 361 antiviral interferon induced protein with multiple domains targeting lipid rafts, mitochondria, and endoplasmic reticulum resulting in inhibition of HCMV, HCV, influenza, HIV,

30

How does IL-1 work?

IL-1α is synthesized as a precursor protein and stored in mesenchymal and epithelial cells but must be synthesized de novo in response to stress. The precursor is modified into a 17-kDa transcription factor, and cytosolic protein which acts as a damage-associated molecular pattern molecule (DAMP). DAMP then stimulates pattern recognition receptors (PRRs) on innate immunity cells, and results in necrosis or pyroptosis of the originally stressed cell.IL-1α stimulates IL-1R

31

What are DAMPs?

DAMP (damage-associated molecular pattern molecules) initiate noninfectious inflammatory responses and include chromatin-associated protein high-mobility group box 1 (HMGB1), major mediator of endotoxin shock; DNA and RNA mediated by TLR9 and TLR3; S100 molecules, ATP, adenosine, and uric acid.

32

What pathways are stimulated after IL-1 receptor activation?

IL-1 stimulates the transmembrane receptor IL-1R, which has many associated proteins including ACCP1, MyD88, IRAK and TRAF6. MyD88, IRAK and TRAF6 also associate with Toll like receptors. These complexes stimulate NIK which then phosphorylates IkB-alpha which is then ubiquinated and destroyed releasing p65 (RelA) and p50 (NF-kB1), transcription factors for inflammatory response-TNFα, INF.

33

What sort of protein is MICA (MHC class 1 chain-related sequence A) ?

MICA (MHC class I polypeptide-related sequence A) encodes a highly polymorphic MHC class I protein that does not associate with beta-2-microglobulin. It is broadly recognized by NK cells, NKT cells, and T cells. It is the ligand that activates the NK cell receptor NKG2D.Alleles of this gene determine rheumatoid arthritis susceptibility.

34

How many types of Treg lymphocytes are there?

Naturally occurring Treg cells (nTreg) are CD4+ CD25+ FoxP3+. Adaptive Treg cells are also known as Tr1, Th3, CD8+CD28+, Qa-1 restricted cells may also contain FoxP3 and function as suppressor cells. Induced Treg cells (iTreg) develop outside the thymus from mature CD4+ T cells, and function to increase TCR diversity.

35

What does thymic stromal Lymphopoietin do?

TSLP (Thymic Stromal Lymphopoietin) induces T cell-attracting chemokines from monocytes that increases maturation of CD11c+ dendritic cells.

36

What are the proinflammatory family members of the IL-1 superfamily?

Proinflammatory IL-1 family members include IL-1 alpha, beta, IL-18, IL 36 alpha, IL-36 Beta, IL-36 gamma and IL-33. Antagonists to other members include IL-1Ra, IL-36Ra, IL-37.

37

How many members are there in the IL-1 superfamily?

The IL-1 superfamily has 11 members currently identified as various forms of IL-1,33,36, 37, and 38. Each one may or may not have a co-receptor as well as a receptor. Some are proinflammatory (7) in some anti-inflammatory (3). 9 members are on chromosome 2q, 1 on chromosome 11, and 1 on chromosome 9.Nomenclature reflects common use rather than systematic structural similarities.

38

Are IL-1 transcripts active prior to proteolytic cleavage?

IL-1 alpha and IL-33 are stored in their long form and are capable of stimulating their receptor. IL-1 beta and IL-18 require proteolytic cleavage by caspace 1 to become active.IL-1 secretion occurs without use of the golgi apparatus.

39

Why is IL-1 alpha considered a dual function cytokine?

IL-1 alpha precursor protein contains a transcription factor (ppIL-1 alpha) released via calpain (calcium activated protease). This activates synthesis of NF-kB, IL-6, TNF alpha and INFγ.

40

how are Tregs cells produced in the gut which permit tolerance to most gastrointestinal antigens?

Tissue resident mononuclear phagocytes produce IL-1 beta which stimulates ILC3 cells (innate lymphoid) which then release Csf2 (GM-CSF). Phagocytes, and dendritic cells then produce IL-10 and retinoic acid which then cause naïve T cells to become Treg cells.ILC3 cells are ROR gamma t+ (RAR-related orphan receptor gamma).

41

What does CCL2 have to do with monocytes?

CCL2 is C-C motif ligand 2 (MCP1 monocyte chemotactic protein 1) belongs to the CC chemokine family that recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation, caused by either injury or infection.

42

What is Helios?

Helios (IZKF2) is a zinc finger transcription factor important in lymphocyte maturation.Other family members include Ikaros, Aiolos proteins.

43

What is the difference between T cell dependent and T cell independent responses?

T cell dependent antibody responses (TD) are elicited by proteins producing B cell activation, proliferation, and antibody production. T cell independent antibody responses (TI) are TI type I (TI-1), which need TLR support and TI type II (TI-2) which rely on extensive cross-linking leading to B cell receptor activation and IgM production.

44

What is the role of endogenous retroviruses in TI-2 antibody responsiveness.

TI-2 responses may be depend upon endogenous retroviral activation, reverse transcriptase activation with RNA becoming DNA, stimulation of the MAVS, RIG-1 and cGAS pathways, which augment antibody synthesis.
Mitochondrial antiviral signaling protein (MAVS) is an adapter for RIG-1-like human helicases (R NFkBicase).
cGMP-AMP synthase (cGAS) catalyzes the synthesis of cGMP-AMP which binds and activates STING leading to type I interferon production.
STING (stimulator of interferon gene) is part of the cytosolic DNA-sensing pathway
The combination of affects stimulates B cell via NFkB via B cell receptor and Btk.

45

What chromosomes code for light and heavy chains?

The heavy chain locus is at 14q 32.33, 1.25 million bases, the kappa light chain is on chromosome 2, about 400,000 bases and the lambda chain is on chromosome 22. about 900,000 bases.
RAG2 (recombination activating gene 2). protein product involved in V(D)J recombination during B and T cell development. Mutations result in Omenn syndrome, a form of severe combined immunodeficiency.

46

What is IgJ?

IgJ is an immunoglobulin, 15 kDa, with typical immunoglobulin beta pleated sheets that binds the alpha chains of IgA and mu chains of IgM.
There are almost 1 trillion B lymphocytes that make more than 1 billion different immunoglobulins.

47

What co-stimulator T-cell system regulates Th17 function?

Inducible co-simulator (ICOS, CD278) is part of the CTLA-4/CD 28 system, expressed on activated T cells, and regulates T follicular helper cells (Tfh) , and IL 23 receptor expression thereby affecting Th17 function. It also has a role in IL-2 secretion.

48

What is tenascin?

Tenascin is an extracellular matrix glycoprotein, 190-240 kDa, 2203 amino acids. The carboxy terminus is similar to fibrinogen. Binds to syndecan. Multiple disulfide bonds and glycosylation sites. The C form is abundant in tendons, bone, cartilage. The R formed in the nervous system, the X form in this connective tissue where mutations resulted Ehlers-Danlos syndrome, and the W formed in the kidney and developing bone.

49

What is viperin (virus inhibitory protein, endoplasmic reticulum-associated, interferon inducible) and how does it work?

viper in works on cell membrane lipid rafts via inhibiting farnesyl diphosphate synthase (FPPS) and isoprenoid synthesis to inhibit virus replication.

50

What are Cathelicidins?

Cathelicidins are 12 to 80 amino acid residue proteins found in lysosomes and neutrophile granules that are increased by vitamin D and have a bactericidal activity. Vitamin D decreases infections in dialysis patients.
They account for inflammation in rosacea where they are released by epithelial cells.

51

what is LFA-1 (Lymphocyte function-associated antigen 1 )?

Lymphocyte function-associated antigen 1 is a heterodimer integrin CD11a (integrin alpha L, p189) and CD18 (integrin beta-2). This is present on both T and B cells and binds to ICAM-1 (CD54) on antigen presenting cells.

52

What is CXCR5 ?

CXCR5 (CD185) is a 7 transmembrane G protein-coupled receptor for CXCL13. Secreted by T cells. CXCR5 is a follicle homing receptor. CD4+ CXCR5+ T cells protect against tuberculosis.

53

What does Bcl-6 transcription factor do?

Bcl-6 B cell lymphoma 6 protein, a zinc finger repressor of IL-4, stimulates T->Tfh