Immunology Exam 1 Review PDF

Immunology Exam 11 Review Chapter 4- Antibody Structure and the Generation of B-Cell Diversity - antibodies : Secreted form of B cell's receptor fo...

Immunology Exam 11 Review Chapter 4- Antibody Structure and the Generation of B-Cell Diversity - antibodies : Secreted form of B cell's receptor for antigen ; clears body of extracellular pathogens and their toxins. Produced by plasma cells. Specific binding (binds to one antigen) - immunoglobulins : cell surface (membrane-bound) antigens + B-cell antigen receptors - clonal selection :. Antigen binds to immunoglobulin adaptive immunity > - B-cell stimulated to proliferate differentiate into plasma cells Secretes large amount of antibody w/ same specificity > > as Ig - -. After a mature B cell encounters its specific antigen , changes specificity and effector function of antibody. STRUCTURAL BASIS (ANTIBODY DIVERSITY) -variable region : contains antigen-binding site , specificity - constant region : interacts with other immune system comp - Isotypes IgG IgM : , , IgD, IgA , IgE (diff constant region structures - heavy chain and light chain : 4 polypeptide chains in antibody - cleavage of IgG : Can be cleared w/ a protease to produce two Fab (fragment antigen binding) which corresponds to the stem Fc (fragment crystallizeable - heavy chain determines isotype - constant region of heavy chains are composed of 3 4 - C domains ANTIGEN BINDING SITES - epitope : part of an antigen to which a particular antibody binds to CLONAL SELECTION OF ANTIBODIES - immunogen/polyclonal antiserum : contains a variety of antibodies specific for diffepitopes of the immunizing antigen - clonal selection : 1) resting mature B-cell expresses membrane-bound antibody (B-cell receptor) 2) antigen binds , B cell stimulated to differentiate into plasma cells. 3) plasma cells secrete antibodies - monoclonal antibody : one clone/type of antibody - flow cytometry : allows cells to be distinguished by cell-surface mouc - monoclonal antibodies used to treat disease  GENERATION OF IG DIVERSITY IN BCELLS BEFORE ENCOUNTER WIANTIGEN - membrane-bound lg made in ER requires both Igo and IgS before transport to surface - 1ga IgM 1gB + B-cell receptor + = -gene segments 19 genes are organized: in fragmented forms arrayed on the chromosome. - alternative versions of same part of IgV region Individual gene segments must be rearranged (rearrangements marrow) - occur during development in. - somatic recombination : during B-cell development , arrays of 19 gene segments are cut + spliced w/ V and J - > light chain gene : single recomb. event gene : double recomb events W/ DH and JH DJ and VH - > heavy chain , then - V genes contain segments the most > recombination ↳ signal sequences (RSS) : flank 3'V , both D , S'J only 12 23 spacers + RAG-1 and RAG-2 (recombination - activating genes : forms functional RAG complex V(D)J , recombinase. The diff length of two arms from RAG-1 ensures 12/23 rule V + J are cut and spliced. - * remember ! Method I for diversifying somatic recomb. is VDJ segments · Mod2 is random incorporation nucleotide of additional during formation of coding joints. GENERATION OF JUNCTIONAL DIVERSITY - steps for additional diversity : 1) RAG cleaves at reptamer sequences Separates D + J. 2) ends of 2 strands of DNA are joined to form hairpins 3) cleared hairpins generate Sequences &D + J 4) TdT adds N-nucleotides 5) single strands pair and repaired to coding joint with Exonuclease , DNA polymerase , + DNA ligase ALTERNATIVE MRNASPLICING IN NAIVE B-CELLS PRODUCES IgM AND IgD OF SAME ANTIGEN SPECIFICITY VDJ rearrangement brings promoter enhancer - + close together, which enables transcription of rearranged gene. - Heavy chain constant regions have u S,. E, a , and y - Naive B-cells express both19m and IgD on the Surface * binding of antigen to B-cell receptor of naive B-cell triggers proliferation + differentiation to secrete large amount of antibody wh same specificity.  IgD on cell surface switch -19m from surface to secreted + antibody SOMATIC HYPERMUTATION - DIVERSITY AFTER B-CELL ACTIVATION ANTIGEN - somatic hypermutation : the whole V domain coding sequence in VH and V are introduced wh point mutations at a high rearranged V regions rate at AID (activation-induced dependent on cytidine deaminase) , which converts (to U generating -. mutations in proliferating B-cells affinity maturation mutations causing higher affinity for : infecting pathogen - ISOTYDE SWITCHING - isotype switching : B-cell changes Ig class it makes while preserving antigen specificity of lg - involves recombination that attaches diff heavy chain constant region to existing variable reg. dependent on AlD and occurs only B-cells proliferating to in antigen response - - > loops out expressedC Genes and brings another C gene to juxtaposition wh assembled v region SECRETED IgM - first antibody made by activated B-cells circular pentameric w/10 antigen binding sites = - Igm : circulates in blood + lymph kill. microorganism? or facilitate phagocytosis - 19A : mucosal surfaces, gut , milk , sweat , saliva , etc. - IgE : epithelium , most cells , inflammation , kill parasites - IgG body : fluids , complement 11 , phagocytes , NK Cells ↳ * highly flexible ! 5  Chapter 5-antigen Recognition by T Lymphocytes COMPARING B& T CELLS - similarities : produced via somatic gene rearrangement highly antigen specific · · T-cell receptor resembles antibody FAB fragment differences : B-cells function to produce various antibodies , T-cells interact whothercells for rolls many · - · B-cells recognize antigens through direct binding to antigen , T-cells via antigen-specific interactions through other cells T-cell. ligand = antigen peptide + MHC B-cells make multiple isotypes of antibodies wh same antigen specificity. No T-cell equivalent · Of isotype switching / hypermutation. One clone of cells expresses one antigen specific TCR T-CELL RECEPTOR DIVERSITY antigens w/ specificity and diversity , one binding site - - similar to FAB fragment, but membrane-bound to T-cell surface - TCR diversity generated by gene rearrangement (none after activat). I ↳ - TCRs have two chains ; a and 3 - In T-cell development in the thymus, - one gene segment in V region is joined to to > gene by rearrangement generate diversity MEMBRANE TCR COMPLEX - - expression of TCR on T-cell surface requires association wh additional proteins - > going from ER to surface requires (D3 Complex > - CD32s + CD3Er + CD333 - more diversity in TCR genes than BCR genes ANTIGEN PRESENTATION FOR TCR RECOGNITION - strict selection for survival - all ligands for TCRs = short peptide and mic Molecule (peptide MHC complex) : - a T-cell is activated once circulating T-cells detect peptide : mic complexes that contain peptides derived from infectious agents. - activated to make adaptive immune response -antigen processing : pathogenic proteins degraded to give peptides to be incorporated into MHC molecules - antigen presentation : peptide MHC complexes delivered : to surface ↑  MHC CLASS 1 MHC Class AND CLASS 11 MHC Class Il S I Il presents intracellular antigens presents extracellular antigens CD8 = Heterodimer degraded in cytosol degraded in lysosomes wI two chains expressed by nucleated cells by antigen-presentationclls cytotoxic T-cell helper - T cells CD4 : single intracellular infection extracellular infection polypeptide w/ express CD8 cell-surface protein express CD4 cell-surface four domains protein kill infected cells secrete cytokines/activate macrophages protects nucleus/cytosol protects vesicular system proteasomes , TAP , PLC , tapasin , invariant chain - MHC Class 1 & ll molecules have similar structures site : MHC fold ↳ similar structures in peptide binding ↳ domains that bind to CD8/CD4 - MHC 1 binds to shorter peptides - promiscuous binding specificity versatility : in binding to peptides w/ very different sequences , - MHC Class 1 and 11 bind peptides in diff intracellular components ↳ II I proteasomes in MHC - proteasomes generate peptides for MHC - damaged proteins marked by Ubiquitin for degradation. Immunoproteasomes have cap - subunits expressed w/ IFNy subunits - TAP in MAC - TAP peptide transporter peptides generated by proteasomes - are transported across ER membrane With TAD MHC Class 1 binds peptides in context of highly specific peptide-loading complex - - protein retains partially folded MHC I H C.. - when mic I assembled , protein replaced. - PLC (Peptide-loading Complex) : helps load peptide transported by TAP - peptide editing by tapasin when binds to MHC 1 , increases of peptides bound affinity for testing. - - When peptide pinds / high affinity , then conformational change , then dissociation of tapas  invariant chain blocks MHC class11 binding - - prevents from binding peptides in ER - in endosomes, invariant chain is degraded and leaves a 24-residue fragment called the CLIP which fills the MH( 11 groove ↑ CROSS PRESENTATION BY DENDRITIC CELLS (MHC 1) -enables extracellular antigens to be presented by MHC - naive CD8 T-cells can't directly kill cells w/MH) 1 : peptide complex - needs activation by APC's (antigen-presenting cells) to become effector T-cells - dendritic culs acquire pathogen and present them on MHC1 , called cross-presentation Chapter 6 - The Development B Lymphocytes ↳ six phases of development DJ) bone(2 1. B-cell precursors in bone marrow acquire antigen receptors through Ig rearrangements (D + J , then V + Negative selection, prevents emergence of mature B-cells to receptors to normal m by. Positive selection , immature 3 B-cells compete for follicles in secondary lymphoid t where they mature., patrolling to detect infection/pathogens I 4. Mature B-cells circulate between lymph , blood , and 2nd t Second-s.,. activation of B-cells by antigen proliferation , of these antigen-specific as a. Differentiation 6 + diversification within clones gives rise to plasma cells , secretes antibodies, + memory B-cells - > PHASE ONE-GENE REARRANGEMENT -gene rearrangements produce immature BC.. wh one HC , one LC > - one 1g/BC antigen receptor hematopoietic stem cells Pro-B cell > pre-Bcell > immature B-cell - - > - - - dependent on stromal cells - apoptosis is default unless there is a positive signal stromal cells promote development - by 1) specific contact and 2) producing growth factors - I Quality control - productive rearrangements maintain a proper HC reading : frame after arrangement - nonproductive rearrangements : changes reading frame to a point where it is no longer functional [ 1st : V-DJ /translation of HC ? )functional It quality 2 checkpoints : rearrangement - control 2nd : surrogate light chain (tests to see if can become B-cell receptor) / funct. LC - allelic exclusion : ensuring no B-cell rearranges both HC copies · Inactivates RAG. Cell expresses are gene copy  - pre-B cells : multiple rounds of gene rearrangement - > clone of 100 resting pre-B Cells * success in LC production leads to BCR assembly of ALLELI) EXCLUSION PXcause E ↳ PHASE TWO - NEGATIVE SELECTION - elimination of potential self-attack - self-antigens healthy : human tissue - self-reactive B-cells : BC w/ potential to respond to self antigens -prevent w/ negative (apop or in activ) signals.. I todeselectiveeliminationa receptor editing assessing compatibility of receptors from successive gene rearrangements of L : - -signed - clonal deletion : some BC exhaust all rearr possibilities without a non-self-reactive receptor. pansive to their antige o successful BCR - - central tolerance : BC leaving marrow are tolerant to so in marrow - peripheral tolerance : tourance to SA outside bone marrow - > PHASE THREE - POSITIVE SELETION - maturation + survival in lymphoid follicles * immature BC - circulate between blood , secondary L t., and. lymph via afferent lymphatics ↓ - stromal cells secrete cytokines , attract immature BC to HEV to primary follick primary follicle in 2nd L. FDCs (follicular dendritic cells) signal t to become B-Cell - : Mature. ↓ mature BC ↳ PHASE FOUR-SEARCHING FOR INFECTION - recirculation via efferent lymph if no specific antigen in follicle - exits lymph node back to lymph/blood 4 PHASE FIVE-FINDING + PHASE SIX-ATTACKING - after antigen encounter in 2nd Lt- > IgM secreting plasma cells in 2nd hypermut, iso switch, affinity staying c t-> somatic -. maturation > - plasma cells end product of B-all dev plasma cells > antibody - = - in + exiting pane marrow : sanatic recomb. / transcription/alt splicing after antigen in 2nd L t. : hypermutation/ alt splicing/iso switch  Chapter 7 - The Development of T Lymphocytes - T-CELLS DEVELOP IN THE THYMUS - originates from stem cells in bone marrow then migrate to thymus -cellular organization : cortex (immature thymocytes) , medulla (mature - T-CELL LINEAGES - two classes of TCR : &B and 28 (as usually in favor) - aB and US T-cell lineages : - double-negative thymocyte : not expressing CD4 Or CD8 double-positive CD4 and CDS - thymocyte expressing : both - MULTIPLE REARRANGEMENTS of pre-T cell -successful B-rearrangement assembly > - proliferation of B-chain DP & self MH) signaling > thymocytes - - - a-chain locks rearrangement (has S-chain , deletion of S = o lineage) ② Pre-T cell - successful d-chain > - ER for testing binding capacity to B-chain ①US - unsuccessful > - apoptosis - > to summarize : 1) If before B-chain JS , then JS cell if ↳ before Uchahthenpre ea ⑪ as ③ US 4)If Cl-chain before US , then as cell most common - POSITIVE + NEGATIVE SELECTION - T-cells that recognize self-mac/peptide undergo positive selection to further develop - thymoproteasome : produces self-peptide positive , selection when bound to MHC - positive selection determines either CD4 or CD8 = selection by MHC Class 1 : CD8 + MHC I are engaged MHC Class 11 : CD4 + MHC 11 - selection by engaged are - single-positive thymocytes after lineage committment, : thymocytes express either CD4 or CDS - committment through protein kinase Lck T-cells that bind too strongly to self-mHC/ Peptides are - eliminated through negative selection - > to summarize : 1) death wh lack of P S.. 2) P S.. for low. affinity for MHc/peptide. for 3) N S. high affinity for MHC/ peptide 4) CD4 vs CD8 ↓ helper killer  Chapter 8-T-cell mediatedImmunity - ACTIVATION OF NAIVE T-CELLS BY ANTIGEN strategy capture pathogen and sequester in secondary L. - :. t - dendritic cells carry antigen from infection site to secondary Lt.. (draining lymph nodes associated to infected mucosal tissue - dendritic cell maturation : dendrites facilitate interactions w/ T-cells in lymph node - immature d C.: skin. + peripheral tissues - mature d C... lymph nodes - ANTIGEN PROCESSING - receptor-mediated endocytosis Captures bacteria/virus from Em and targets them to lysosomes : macropinocytosis : endocytosis of larger volumes of fluid/ pathogens unrecognized by receptors - ↳ non-receptor mediated - Naive T-cells encounter antigen presented by d - T-cell zone : Outermost part of lymph node cortex , - lymph node interact w/ mature naive enter , d C.. enters X-TCR probe peptide : MHC complexes an d.. C thrn blood surface to find antigen or afferent lymph antigen receptor of TC binds to pep : MHC -.. and T-cell is selected to stay in lymph node and activated by d.. c node antigens trapped in draining lymph - increases chances to meet TC.. Homing of Naive T-cells to draining L N. =. - homing : process by which naive T-cells leave blood stream and enter T-zone - involves all four types of cell-adhesion molecule - homing guided by chemokines conjugate pair : ac + naive antigen- - specific T-cell come together - > T-cell proliferates into effector TC - Sphingosine-1-phosphate (SIP) : eff. TC leave lymph nodes departure , controlled by SAP - ACTIVATION OF NAIVE T-CELLS WISIGNALLING J - from antigen receptor + co-stimulatory signal multiple interactions - > TCR + CD418 - CD28 Stimulate T-cell prolif + diff recognizes pep : mic recognizes BT molecule FC and DC T-cell synapse : region of contact/communication between - -supramolecular activation Complex (SMAC) : structure to concentrate TCR , CO-R , co-StimR , adhesion/signaling molecules - clustered interactions trigger signaling via phosphorylation > - TC diff. mHCI) - ~ MHC - B7  - Interleukin-2 (IL-2) : drives prolif + diff of activated i - Naive + activated TC have diff Il-2 - > activated FC has higher affinity for 11-2 ↳ acts in an autocrim fashion cytokine that acts : on same all that secreted it - antigen recognition who co-stimulation leads to anergic iC (unresponsive) - ACTIVATION OF NAIVE CD4 TC GIVES RISE TO 5 TYPES OF EFFECTOR TC (HELPER-T) 1. Th1 : activates macrophage. Th2 2 : activates response to parasites. Th17 3 : neutrophil response 4. TFH : activates B-cells effector TC. 5 Treg : suppress other * inhibitory - ACTIVATION OF NAIVE CD8TC INVOLVES IL 2 = needs activation than CD4 stronger - - z ways : 1) CD8 TC can be directly activated by a virus-infected d.. C 2) d C that induces insufficient.. co-stim can be helped by 1-2 secreted by CD4 TC to boost CD8 activation - EFFECTOR PROTEINS effector made effector iC delivered to target cells via synapses - proteins by - 2 types : cytokines : alter behavior of target all via gene regulation CytotoXMs : kill target cell - cytokines received by cytokine receptors , transduce signals to regulate gene expression - binds JAKs , assembles then phosphaylates receptors , phosphorylates , STAT initiate exp. - CD8 TC ARE SERIAL KILLERS OF TARGET CELLS AT INFECTION SITES - targeted release of cytotoxins - cytotoxic TC detach when target cell is dying - can Secrete IFN-N which inhibits viral replication + activates macrophages - THI CD4 ENHANCE MACROPHAGE FUNCTIONS macrophage activation : fusing phagosomes more efficiently w/ lysosomes increase microbicidal more. - , - Th1 activates macrophage - Th2 suppresses macrophage activation