fast_track_review_september_2024.pdf

MI| Blood & Immunology BI-xXx Fast-Track Review– EXAM 2024 JEAN-ERIC GHIA, PHD, HDR DEPT. OF IMMUNOLOGY & INTERNAL MEDICINE SECT. OF GASTROENTEROLOGY APOTEX 431, 204-789-3802 [email protected] 1 Disclaimer Note that unless othe...

MI| Blood & Immunology BI-xXx Fast-Track Review– EXAM 2024 JEAN-ERIC GHIA, PHD, HDR DEPT. OF IMMUNOLOGY & INTERNAL MEDICINE SECT. OF GASTROENTEROLOGY APOTEX 431, 204-789-3802 [email protected] 1 Disclaimer Note that unless otherwise indicated, all images are from previous sessions and have been obtained from the digital version of the textbook, which is available in the Medical Student Toolkit via ClinicalKey. 2  Don’t forget to learn the terms presented in the 2024 updated glossary. - Don’t memorize word for word but know what they mean! Notion 1 The lymphatic system  How does the lymphatic system compare with the circulatory system with Notion 2 respect to the flow of fluid? The lymphatic system has no built-in “ pump” such as the heart in the circulatory system, but other mechanisms help keep lymph flowing, so the movement of lymph is a bit more sluggish than blood. The lymphatic and circulatory systems are connected – fluid can leave the blood and enter the tissue, then move into the lymphatic vessels and lymph nodes, eventually making its way back into the blood at the thoracic duct. The lymphatic vessels contain valves to ensure the unidirectional flow of lymph. The larger lymphatic vessel walls contain smooth muscle, which can contract to help the lymph to flow. Muscular contractions also assist with the movement of lymph. Notion 2 The spleen  2 types of circulation? Closed circulation: The blood empties from the vessels of the white pulp into sheathed capillaries of the red pulp and then directly into the sinuses. Open circulation: The blood empties from the sheathed capillaries into the splenic cords (empties into spaces between the reticular cells of the red pulp outside the sinus) and then enters circulation through slits in the sinus wall.  Do we need to know the different vessels? Yes, you need to know the all sequence. Notion 3 Complement system  Complement System – What do we need to know?? Major concepts you need to know… How the complement cascade is triggered - alternative vs. classical pathways. (You should also recognize that the response is amplified as it develops.) What the products are and what they do (e.g. C3a, C5a, C3b, C5b, MAC complex.) How the cascade is regulated. What some of the common deficiencies in complement or complement regulatory proteins are and the conditions that are typically seen in people with these deficiencies. What the common clinical tests for complement are?  What are the three different pathways ? Are they leading to the same finale activation process ? Not intracellular events, but external membrane bound events The complement pathway are : Alternative pathway Classical pathway Lectin pathway https://www-clinicalkey-com.uml.idm.oclc.org/#!/content/book/3-s2.0-B9780323390828000089?scrollTo=%23hl0000278  What are the three different pathways ? Are they leading to the same finale activation process ? C1-inhibitor, also called C1 esterase inhibitor, is a protease inhibitor belonging to the serpin superfamily. Its primary function is the inhibition of the CS to prevent spontaneous activation. The C1-inhibitor irreversibly binds to and inactivates C1s and C1r proteases within the C1 complex. The result is that C1-inhibitor will prevent the proteolytic cleavage of later complement components C4 and C2 by C1complex. For example, hereditary angioedema is caused by continued complement activation resulting from a mainly genetically determined deficiency of an inhibitor of the enzyme C1 esterase, thus, C4 is consumed, and its plasma level falls. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/allergy/hereditary-angioedema/ Notion 4 Antigen-presenting cells  Can an APC present Ag to a B cell?? & what are FDCs?? Yes….but not in the way they present Ag to T cells… Follicular dendritic cells (FDCs): Support the architecture of the follicles in the secondary lymphoid tissues. Hold on to intact antigen for a long time – typically in the form of immune complexes (Ag + Ab) bound to their Fc receptors. In contrast to APCs that present Ag to T cells, FDCs don’t internalize or process the antigen. Instead, they present the intact Ag to B cells. B cells must be presented with intact Ag by FDCs to differentiate into memory cells or Ab-secreting plasma cells. If this doesn’t happen, the B cell dies by apoptosis.  How APC recognize Ag ?? And how much do we need to know about the different TLR’s (eg. which TLR's bind what molecules)?  Which cells express B7 vs CTLA4? CTLA-4 (known as CD152) can downregulate the immune response. CTLA-4 is constitutively expressed in Treg cells but only up-regulated on T cells after activation, and it will bind to B7 on antigen-presenting cells. Notion 5 MHC Not sure if emphasized enough Class I MHC is expressed on virtually all nucleated cells (so not on red cells) => CD8. 1 x 8= 8 Class II MHC is expressed on “professional” APCs => CD4. 2x4=8  Where are they located? Chromosome 6 – one from mom and one from dad, both alleles for each HLA locus are expressed.  Are there multiple MHC's (beyond MHC I and MHC II) or do MHC I and II just have variability in the region that binds/presents antigen? i.e. how do we get the extensive repertoire in MHCs? You could have two different HLA molecules for HLA-A, B, and C (class I) and HLA-DP, DQ and DR (class II) since maternal & paternal alleles are expressed – so… up to 6 different MHC molecules for class I and II combined. Recall: You can derive many different antigenic peptides from one pathogen once it’s been phagocytosed and processed. Each HLA molecule can only present one peptide at a time, but it can fit many different peptides as long as they fit in the groove and become adequately anchored. This is critical because each person has only a few different MHC molecules. Notion 6 T cells  Type of T-cell receptors ? Co-stimulator i.e CD28/B7 Fig. 4.7 22  Do naive T cells become Helper T cells before they are activated to proliferate by an antigen? No, when T cells are first presented with antigen by an APC, several intracellular signaling pathways are triggered (with the help of CD3, co-stimulatory interactions, etc.). The first cytokine produced is IL-2, which induces proliferation. As the T cell proliferates, it starts to differentiate into an effector T cell (e.g. Th cell or CTL). Factors that help to determine what subset a Th cell will become committed to are: type of antigen, cytokines produced by innate immune system and transcription factors turned on early in T cell differentiation. Recall that cytokines from one Th subset inhibit the development of the others.  Do we need to remember all the CD markers ? No, there are over 300 markers today, and some are discovered daily. Remember, C3, CD4, CD8, B7 (C86, CD80), CD40, CD19, 20, 25 and 56 (NKC)  Lymphoid tissue interactions  B cells can further activate previously differentiated effector T cells but are not very T cell is recognizing antigens on an APC and becoming good at activating naïve T cells. either a Th cell or a CTL (effector cell) here See slide about Follicular DC Long-lived plasma cells Proliferating B cells. B cell activation and Somatic hypermutation Early antibody responses Class switching – stronger and more effective Ab26responses Notion 7 B cells  Does class-switching occur at the DNA level or at the mRNA level? It occurs at the DNA level. The exception is IgM and IgD, which involve alternative splicing of mRNA  When a pre-B cell gets turned into an immature B cell, does that small light chain section disappear and get replaced by the actual light chain (due to rearrangement of the Ig light chain variable region genes)? The VpreB gene encodes the iota polypeptide chain associated with the Ig-mu chain to form a molecular complex expressed on the surface of pre-B cells, presumably regulating Ig gene rearrangements in the early steps of B-cell differentiation.  How do memory B cells develop? Are they antibody-producing Notion 3 plasma cells that have developed memory and survive after the infection? Sequence of events in the development of a humoral immune response Memory B cells develop from mature, activated, antibody-expressing B cells that receive pro-survival signals and migrate back to the bone marrow. The plasma cells are relatively short-lived. 30  Difference between T-cell dept & dept B cells ? T-cell dept B cells: Antigen uptake and processing plus B cell activation will happen within the primary follicle; when done, B cells will migrate to the paracortex and meet with activated T cells T-cell Indep B cells: Stay within the marginal zone.  Difference between monoclonal vs clonally distributed ? They are two different concepts. Usually, it would help if you compared monoclonal to polyclonal. A Polyclonal Antibody represents a collection of antibodies from different B cells that recognize multiple epitopes on the same antigen. Each of these individual antibodies recognizes a unique epitope that is located on that antigen. Conversely, a monoclonal antibody represents an antibody from a single antibody-producing B cell and only binds with one unique epitope. Each individual antibody in a polyclonal mixture is technically a monoclonal antibody! However, this term generally refers to a process by which the actual B-cell is isolated and fused to an immortal hybridoma cell line so that large quantities of identical antibodies can be generated. For more details: https://academic.oup.com/ilarjournal/article/46/3/258/738903 Clonal selection is a part of the human immune response where specific B or T-helper lymphocytes are chosen to undergo clonal expansion. Notion 8 Class-Switching  For antibody-dependent cell-mediated cytotoxicity (ADCC) to be activated (for NK cells), does it require complement system to coat the Antigen first? No, just antibody. In the case of ADCC who is secreting the Antibodies then? B cells (with help of class II MHC)? Yes, B cells with CD4+ T helper Cells providing cytokine support. So, in a way NKs are part of Innate system, but will work after activation of adaptive system (both in ADCC and also in normal killing)? Yes! Figure 8.5 in Abbas textbook  How much do we need to know about the different AB? Notion 9 Complement & Adaptive Immunity  What is the specific relationship between the Complement System and Adaptive Immunity? The complement system is an enzymatic cascade in which several proteins (the complement proteins) participate. It is part of the innate immune system. One major function is to “label” pathogens for elimination (opsonins). There are a few ways that complement can influence the development of some adaptive immune responses. One way is by inducing inflammation, which has many effects, including increased immigration of leukocytes (neutrophils and monocytes, then lymphocytes later on) into the inflamed tissue. Inflammation also enhances antigen presentation to T cells.  What is the specific relationship between the Complement System and Adaptive Immunity? Activation of the classical pathway involves antibodies produced by the adaptive immune system. (e.g. Immune complexes made up of antibody molecules cross-linked by antigen are very good at activating the complement cascade via the classical pathway.) Complement can also be involved in B cell activation (see previous slides), providing another link to the adaptive immune system. The lectin and alternative pathways provide “antibody-independent” innate defence. Notion 10 Immune Complex Y YY Y YY YY  When are memory T cells made - After T cell activation or after T cell differentiation into Th1, Th2 and Th17? After both have occurred! Into Th subset  It appears that helper T cells have already differentiated into antigen-specific cells before they see peptide antigen that has been presented by the MHC on a B cell. Yes, this is correct because they have TCR (Ag-specific receptors) when they leave the thymus and typically encounter B cells in the peripheral lymphoid tissues. Notion 11 T reg  How Treg are produced? Tregs can interact with APCs and inhibit their ability to activate other T cells by engaging their CTLA-4 with the APC’s B7 molecule. They can also deplete B7 expression on the APCs. Notion 12 Cytokines  Do we need to know all the cytokines and their receptors? No….but you need to know the major one released by APC and implicated in the T cell polarization… Defining cytokines INF-g IL-4 IL-5 IL-13 IL-17 IL-22  Are th1 cytokine inhibiting Th2 and Th2 inhibiting Th1? Yes they are! Cytokines produced by one Th subset inhibit the development of the other subsets, so polarization occurs. Notion 13 Development  It is there a difference between B/T negative selection and B/T central tolerance? Central tolerance is also known as negative selection. Notion 14 B and T cells interactions  Lymphoid tissue interactions  B cells are capable of further activating previously differentiated effector T cells but T cell is recognizing antigen on an APC and becoming are not very good at activating naïve T cells either a Th cell or a CTL (effector cell) here See slide about Follicular DC Long-lived plasma cells Proliferating B cells. B cell activation and Somatic hypermutation Early antibody responses Class switching – stronger and more effective Ab51responses Notion 15 NK Cells  Functions of NK cells Direct: Killing of infected cells Indirect: Killing of phagocytosed microbes via the release of INF-g Notion 16 T cells development  T-cell developpment + Why does no binding lead to apoptosis, shouldn’t T-cells not want to bind to self antigens to prevent autoimmunity? And why does weak binding of self antigens need to occur for T-cells to be selected. + I understand why you would want to select against T cells who strongly recognize self antigens found in the thymus, but why would we want to also select against T cells who don’t recognize self antigens at all? Aren’t these T cells ideal since they don’t react with our own body at all? And along the same line why would we positively select T cells with low to moderate self reactivity? It’s a bit confusing. If you check chapter 4 from the book: https://www-clinicalkey-com.uml.idm.oclc.org/#!/content/book/3-s2.0-B9780323549431000040 In the end, the authors raise the same kind of question and give a brief explanation. See below copy/past: "It may seem surprising that both positive selection and negative selection are mediated by recognition of the same set of self MHC–self-peptide complexes in the thymus. The two factors that determine the choice between positive and negative selection are the affinity of the TCR and the concentration of the self-antigen in the thymus. If a TCR strongly recognizes an abundant self-antigen in the thymus, that T cell will be negatively selected, which makes sense because strong recognition of an abundant self-antigen has the potential for causing autoimmunity. However, if a TCR weakly recognizes a self-peptide–self MHC complex, that T cell will be positively selected because there is a reasonable chance the T cell will recognize a foreign peptide presented by self-MHC strongly. This process gives rise to the repertoire of functional T cells.” Notion 17 FAS FasLigand  Where the FAS and FASL are expressed? They can be expressed on the same cell, and multiple combinations and interactions between different kinds of cells are possible. Notion 18 Complement …again!  The figures in the book are not clear enough? Old nomenclature C3 convertase can be : C4b2a or C3bBb C5 convertase can be: C4b2a3b or C3bBb3b New nomenclature: 2a has been replaced by 2b C3 convertase can be : C4b2b or C3bBb C3 convertase C3 convertase C5 convertase can be: C4b2b3b or C3bBb3b C5 convertase Notion 19 T cell development Maturation & Selection of T-Cells | Step 1 | Early Steps in T-Cell Maturation phase 1e 1 1 Double Negative | T cell progenitors migrate from the bone marrow to the thymus to undergo maturation. Pro-T cells lack CD4 and CD8 and The book presents IL-7 as the cytokine responsible for proliferation. And it’s correct. are called “double negative” cells. However, Il-17 can be implicated in double-negative T –cell in the context of inflammation. They can expand under INF-g or IL-17 in vitro. See reference Expansion is under IL-7 or IL-17 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003441 in the context of inflammation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596652/ Antigen Recognition in the Adaptive Immune System: Structure of Lymphocyte Antigen Receptors and Development of Immune Repertoires Abbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 4, Figure 4.14 Copyright © 2024 by Elsevier Inc. All rights reserved. 61 Notion 20 Mucosal Immunity IgA exhibit extensive cross-reactive (‘innate-like’) activity which provides cross-immunity and herd protection sIgA2 isotype is resistant to proteolysis (bound secretory component (SC) stabilizes both isotypes) Exhibit mucophilic and lectin-binding properties (via bound SC in both isotypes, and mannose in sIgA2) At the mucosal level, IgA targeting a specific antigen can also detect some antigens which have a very close sequence to the initially detected antigen. Here we are talking about IGA as they are the main ones released at the mucosal level. Also, you need to take into consideration the configuration of the antibody as a dimer. Why? Due to the environment, you will have a lot of enzymes that would normally destroy monomeric antibodies. Finale Notion Am I ready for the exam? YES!!!