Molecular Disease Mechanisms 1 Molecular Disease Mechanisms 2 Adaptive Immunity A Few Notes Hematopoiesis Molecular Disease Mechanisms 3 Adaptive Immunity Molecular Disease Mechanisms 4 Adaptive Immunity Innate vs. Adaptive Immunity Cardinal Features of Adaptive Immune Response Main Stages of B Cell Development 2 Antwort 1 Antwort • production of 1011 cells per day Hi there, fellow biologist! I made these cards for the exam of the spring semester 2018 and thought I could improve my karma a bit by sharing them. They are probably not com- plete/won't entirely cover the next iteration of the course but they should be hella helpful. If you are wondering how i made these beauties, it's all made with LATEX- which I would highly recommend you to take a look at. And if you want to expand or change them or just for telling me what a wonderful person I am for sharing my hard work, send me an email at [email protected] and I'll send you the original LATEXfiles Cheers and best of luck, Pia PS: They have a lot of typos, sue me. 4 Antwort 3 Antwort • Specificity: mediated by specific receptors expressed on B cells (BcR) and Innate Immunity Adaptive Immunity T cells (TcR) lag time between exposure and max- immediate response (min, h) imal response (+/- 7 days) • Diversity: B and T cell receptors have great variability due to DNA rear- limited specificity - can distinguish highly antigen-specific rangements between different types of pathogens exposure results in no immunologic exposure results in immunologic • Clonal Expansion: B and T cells that recognize antigen become acitvated memory - no difference between pri- memory - secondary response faster and proliferate mary and secondary response and stronger • Self limitation: response wanes elimination of antigen • Memory: second response is faster and stronger than first • Self/Non-Self Discrimination Molecular Disease Mechanisms 5 Adaptive Immunity Molecular Disease Mechanisms 6 Adaptive Immunity Development of B cell after antigen encounter Recogniton of Antigens by T and B cells & Clonal Selection & Epitopes Molecular Disease Mechanisms 7 Adaptive Immunity Molecular Disease Mechanisms 8 Adaptive Immunity Antigen Presenting Cells (APCs) - & TcR MHC I & MHC II Protein Composotion 6 Antwort 5 Antwort • B cells recognize epitopes of tertiary structure proteins 1. antigen binds to membrane IgM • T cells recognize processed antigens - peptides - presented by self MHC 2. cell gets activated and divides many times ! clonal expansion • epitope: or antigenic determinant - discret site on antigen that gets rec- 3. B cells mature into plasma cells ! secret antibodies - up to 2000 anit- ognized, immunologically active regions on antigen that bind B- or T-cell bodies/sec/cell receptors Clonal Selection • only cells that are able to recognize foreign antigens due to a fitting B or T cell receptor get activated and proliferate 8 Antwort 7 Antwort • denritic cells (DCs), macrophages (MΦ), B cells • express MHC class I and class II • foreign antigen binds to their MHC ! activate naive T cells • are infected by or internalize antigen ! process antigen by disgestion ! display peptides of antigen in context with MHC on cell surface • TcR (T-cell receptor) recognizes small peptides (8-20 aa) of proteins presentend by major histocompatibility complex (MHC) on APC • CD4 T helper (Th) cells interact with MHC II, CD8 cytotoxic T cells (CTL) interact with MHC I Molecular Disease Mechanisms 9 Adaptive Immunity Molecular Disease Mechanisms 10 Adaptive Immunity MHC diversity and inheritance Antigen Processing and Presentation & Molecular Disease Mechanisms 11 Adaptive Immunity Molecular Disease Mechanisms 12 Adaptive Immunity Presentation of Antigens on MHC I to CD8 T-Cells Presentation of Antigens on MHC II to CD4 T-Cells 10 Antwort 9 Antwort 1. fragmentation of protein into peptides • human: HLA genes, mouse: H2 genes 2. association of peptide with MHC molecule • diversity of MHC exists at the level of the species 3. transport to cell surface for expression • stems from polymorphism (influence of more than one gene) and polygeny (more than one allele in population) 4. different cellular pathways for association of peptide with MHC class I and class II molecule • diversity mainly affects peptide-binding cleft • MHC II: recognizes exogenous antigens & interacts with Th cells that secret • MHC genes expressed from both inherited alleles ! co-dominant expression cytokines • peptides are bound with different affinities by MHC • MHC I: recognizes endogenous antigens & interacts with CTL cells that then • the more different the MHC genes of parents, the better protected are the chil- kill APC dren from infectious disease ! greater chance to recognize diverse pathogen structures ! HLA smell 12 Antwort 11 Antwort • endocytic processing pathway: antigen ingested by endocytosis or phago- • derived from self or infection with viruses and bacteria cytosis ! transport to endosome ! fusion with lysosome ! recognition by MHC II in vesicle ! transport to cell surface and presentation 1. partly folded MHC I α chains bind calnexin until β2-microglobulin binds • MHC II α and β chains are produced and complexed with polypeptide - 2. MHC class I α : β2m complex is released from calnexin, binds a complex invariant chain (Ii) - that blocks its peptide-binding cleft ! Ii facilitates of chaperone proteins (calreticulin, Erp57) and binds to TAP via tapasin export of MHC II from ER to golgi ! fusion with late endosome ! breakdown of Ii leaving only small fragment called CLIP - maintains blockage of binding 3. cytosolic proteins are degraded to peptide fragments by the proteasome cleft ! CLIP is removed and binding of peptides with higher affinity is allowed 4. TAP delivers a peptide that binds MHC I and completes its folding ! folded MHC I is released from TAP complex and exported Molecular Disease Mechanisms 13 Adaptive Immunity Molecular Disease Mechanisms 14 Adaptive Immunity Handling of Cytosolic, Intravesicular and Extracellular Self MHC Restriction Pathogens Molecular Disease Mechanisms 15 Adaptive Immunity Molecular Disease Mechanisms 16 Adaptive Immunity Types of Grafts & T-Cell Maturation Host vs. Graft (and vice versa) Disease 14 Antwort 13 Antwort • T-cells recognize foreign antigen associated with self MHC ! T cells associ- ated with foreign MHC are not recognized • self MHC restriction occurs in thymus • a particular TcR is specific for both antigenic peptide and self MHC-molecule ! only then killing occurs (otherwise poor killing) 16 Antwort 15 Antwort • T-cell generation in bone marrow and fetal liver • Allograft: allotransplantation - grafts between two members of the same species • occurs in thymus • Isograft: graft between members of species with identical genetic makeup • 96% of cells die here without inducing any inflammation by apoptosis (e.g. identical twins) • thymic macrophages phagocytose apoptotic thymocytes • Graft vs. Host: immunocompromised host grafted with foreign immuno- competent lymphoid cells ! T-cells of graft recognize foreign antigens of host • maturation involves change of expression of TcR-associated molecules and ! damage host tissue co-receptors ! can be used as markers for stage of maturation • Host vs. Graft: immunocompetent host recognizes foreign antigens of grafted tissue ! immune response ! rejection of transplant ! Allograft Rejection Molecular Disease Mechanisms 17 Adaptive Immunity Molecular Disease Mechanisms 18 Adaptive Immunity Process of Self MHC Restriction in Thymus Mechanism for Induction of Central T-Cell Tolerance Molecular Disease Mechanisms 19 Adaptive Immunity Molecular Disease Mechanisms 20 T-Cell Response Summary T-Cell Selection in Thymus T-Cell Propagation & Activation 18 Antwort 17 Antwort • AIRE (autoimmune regulator) Transcription Factor: master regulator of • thymus accepts T-cells that fall into a narrow window of affinity for MHC ectopic (abnormal location) expression of peripheral tissue-restricted antigens molecules: interaction too weak or too strong ! apoptosis in stromal cells of thymic medulla • positive selection: T-cells with TcR recognizing are retained • allows for expression of antigens to which T cells are negatively selected ◦ peptide is a partial agonist ! thymocytes receive a partial signal and is • AIRE-/- mice exhibit wide spread organ-specific autoimmunity, such as ovary, rescued from apoptosis retina, testis, stomach ! defect in AIRE gene leads to defect in thymic se- lection and autoimmunity ◦ selection for survival and maturation • negative selection: retained T-cells with TcR recognizing self peptide as- sociated with self MHC are eliminated ◦ peptide is agonist ! thymocyte receives a powerful signal and undergoes apoptosis • self MHC-restricted T-cells are released 20 Antwort 19 Antwort • CD4+ and CD8+ cells leave thymus and enter circulation ! in resting state: Property Positive Selection Negative Selection G0 of cell cycle Site Cortex Medulla Stromal cells in- Macrophages and dendritic Epithelial cells • naive cells circulate between blood and lymph system every 12-24h volved cells Elimination of thymocytes • CD4:CD8 T-cell ratio in lymphoid organs ≈ 2:1 Survival of thymocytes Selection mecha- bearing high-affinity receptors bearing receptors for nism for self-MHC alone or self- • activation of naive T-cells results in primary response: self-MHC antigen + self-MHC after 24h: initiation of repeated rounds of cell division and differentiation Immune conse- Self-MHC restriction Self-tolerance into: quence Effector cells: cytokine producers, cytotoxic killers