Summary
Highlights
The speaker, Khalid Jamir, a fourth-year medical student, introduces an immunology crash course covering lectures 1 to 8. He emphasizes that immunology is an easy topic made difficult by condensed slides, urging students to understand concepts rather than just memorize. The course begins by explaining that all blood cells originate from hematopoietic stem cells, which differentiate into myeloid and lymphoid progenitors. Myeloid progenitors give rise to cells like monocytes and neutrophils, while lymphoid progenitors produce natural killer cells, T cells, and B cells. The innate immune system, present at birth, provides an immediate, non-specific response, while adaptive immunity requires prior antigen exposure, is antigen-specific, and provides a stronger response to subsequent infections due to memory cells.
The innate immune system comprises anatomical (skin, mucous membranes, flushing processes), biochemical (fatty acids, acidic pH, lysozymes), and biological (normal microbiota) components. Normal microbiota compete for nutrients, occupy space, and produce antimicrobials. Blood components like acute phase reactants (e.g., mannose binding lectin), complements, cytokines, lactoferrin, and the coagulation system also contribute. Innate immune cells recognize pathogens through Pattern Associated Molecular Patterns (PAMPs) on pathogens and Pattern Recognition Receptors (PRRs) on immune cells. PAMPs include Microbial Associated Molecular Patterns (MAMPs) like LPS, and Danger Associated Molecular Patterns (DAMPs) which signal cellular damage (sterile inflammation). PRRs include Toll-like receptors (TLRs) for MAMPs, Nod-like receptors (NLRs) for DAMPs (forming inflammasomes to activate IL-1 and IL-18), and Rig-like receptors (RLRs) for viral DNA.
The cellular components of innate immunity are categorized by function. Phagocytosis is performed by neutrophils, macrophages (monocytes in blood, various names in tissues like Kupffer cells in the liver), and dendritic cells. Neutrophils phagocytose but do not present antigens, releasing NETs upon death to alert other cells. Macrophages are associated with CD14 on their surface. Dendritic cells are professional phagocytic and antigen-presenting cells crucial for activating adaptive immunity. Antigen presentation to activate adaptive immunity is mainly done by macrophages and dendritic cells, and importantly, B cells can also act as antigen-presenting cells, a key distinction from neutrophils. Cytotoxicity, direct cell killing, is performed by Natural Killer (NK) cells (CD56/CD16 marker) which target virus-infected and cancer cells. Allergy and hypersensitivity are mediated by eosinophils, mast cells, and basophils.
Adaptive immunity involves primary lymphoid structures (bone marrow for B and T cell production; bone marrow for B cell maturation, thymus for T cell maturation) and secondary lymphoid structures (lymph nodes, spleen, MALT) for lymphocyte activation. There are two types: humoral immunity (antibody-mediated by B cells) and cell-mediated immunity (direct cell killing by cytotoxic T cells). Helper T cells (CD4+) activate B cells, while cytotoxic T cells (CD8+) directly kill infected cells using perforin and granzyme. An antibody consists of four chains: two identical heavy chains and two identical light chains. Each chain has constant and variable regions. The FC (constant) region determines the antibody isotype (IgM, IgG, IgA, IgE, IgD), while the FAB (variable) region determines antigen specificity. The C-terminal of the heavy chain dictates whether the antibody is membrane-bound (BCR) or secreted. CDRs (Complementary Determining Regions) within the variable regions are responsible for antigen binding specificity, with CDR3 being the most important for variability.
Affinity refers to the strength of binding between a single antibody binding site and an antigen epitope. Avidity describes the total binding strength, considering multiple binding sites (valency). For example, a monomeric antibody is bivalent, while IgM exists as a pentamer (10 binding sites) and IgA as a dimer (4 binding sites), giving them higher avidity despite potentially lower affinity per binding site. Antigens are classified into immunogens (large enough to stimulate an immune response) and haptens (too small to stimulate a response alone but can become immunogenic when conjugated to a carrier protein, which increases their size).
Five main antibody isotypes exist: IgM is the primary response antibody, existing as a pentamer/hexamer with low affinity but high avidity. IgG is the major secondary response antibody, with high affinity but low avidity. It has the longest half-life due to binding the neonatal FC receptor, allowing it to traverse cells (and the placenta). IgA provides mucosal immunity and is the most abundantly produced globally but not in the blood, often excreted in bodily fluids. IgE is crucial for allergic reactions and parasitic infections, having the shortest half-life in circulating form but staying long when bound to mast cells. IgD is mainly found as a B cell receptor (BCR) on naive B cells and is not secreted. Antibodies function via opsonization (IgG tags pathogens for phagocytosis), neutralization (blocking viruses from infecting cells), triggering the complement system, and antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells (via CD16).
B cell development in the bone marrow involves VDJ recombination and junctional diversity to create diverse antigen-binding sites. This process randomly combines Variable (V), Diversity (D), and Joining (J) gene segments for the heavy chain and VJ segments for the light chain, orchestrated by RAG1/RAG2 enzymes and TdT (adding/deleting nucleotides), leading to highly variable antibody repertoires. Allelic exclusion ensures each B cell expresses only one maternal or paternal heavy chain and one kappa or lambda light chain. The developmental stages include: pro-B cell (earliest committed cell, expressing CD19), pre-B cell (expresses early IgM with mu heavy chains and surrogate light chains, undergoes successful test run and expansion), and immature B cell (expresses IgM with specific light chains, undergoes positive and negative selection to ensure it binds non-self and not self-antigens, known as central tolerance). Mature B cells, called follicular cells, express both IgM and IgD and are considered naive until antigen exposure. B1 cells are T-cell independent, producing only IgM, similar to innate cells; B2 cells are T-cell dependent and adaptive, capable of producing all antibody isotypes with T cell help.
T cells have two subtypes: CD4+ helper T cells and CD8+ cytotoxic T cells. All T cells express CD3. The T cell receptor (TCR) has alpha and beta chains, analogous to antibody light and heavy chains, respectively, and is associated with CD3 for signaling. Major Histocompatibility Complex (MHC) molecules present antigens. MHC class I (HLA-A, -B, -C) is found on all nucleated cells and presents intracellular antigens (viral, tumor, misfolded proteins) to CD8+ T cells. If an MHC class I molecule presents a non-self antigen, the CD8+ T cell kills the cell. MHC class II (HLA-DP, -DQ, -DR) is found only on professional antigen-presenting cells (macrophages, dendritic cells, B cells) and presents extracellular antigens to CD4+ T cells. MHC class I processing involves ubiquitination of abnormal proteins, breakdown by proteasomes, transport into the ER via TAP protein, loading onto MHC I with tapasin, and presentation on the cell surface. Viruses can evade this by inhibiting MHC I presentation.
MHC class II antigen presentation begins with phagocytosis of extracellular pathogens, forming an endosome that fuses with a lysosome to become a phagolysosome where antigens are processed. MHC class II molecules are produced in the ER, bound to an invariant chain (containing CLIP) to prevent premature antigen binding. The MHC II-invariant chain complex traffics to the phagolysosome, where HLA-DM facilitates the removal of CLIP and loading of processed antigen onto MHC II. The MHC II-antigen complex is then presented on the cell surface to CD4+ T cells, which then release cytokines to activate B cells. T cell development occurs in the thymus, involving VDJ recombination for the beta chain and VJ for the alpha chain of the TCR. Developing T cells (thymocytes) undergo positive and negative selection (central tolerance) in the thymus to ensure they recognize self-MHC but not self-antigens. Mature naive T cells then migrate to secondary lymphoid organs (e.g., lymph nodes) via CCR7 chemokine receptors. Upon activation in lymph nodes, they become effector T cells, proliferating and migrating to infected tissues.
Naive T cells require four signals for activation into effector T cells within lymph nodes. These include: 1) TCR binding to an MHC-antigen complex (signal 1), 2) CD28 on the T cell binding to CD80/CD86 (B7 proteins) on the antigen-presenting cell (APC) (costimulation, signal 2), 3) ICAM-LFA1 interaction for adherence, and 4) cytokines from the APC (e.g., IL-2 for proliferation, signal 3). Immune responses are also regulated. Downregulation can occur when T cells express CTLA4, which competitively binds to CD80/CD86, inhibiting activation. Another mechanism is PD-1 on T cells binding to PD-L1 on APCs, which inhibits TCR signaling. Upregulation of immunity happens through CD40L on T cells binding to CD40 on APCs, leading to increased CD80/CD86 expression, MHC expression, and cytokine production, thereby boosting the immune response.
The complement system is a group of proteins synthesized in the liver, circulating as inactive zymogens that require cleavage for activation. Its functions include opsonization (C3b and C4b tag pathogens), anaphylatoxins (C3a, C4a, C5a induce allergic reactions by binding to mast cells and causing histamine release), chemotaxis (C5a attracts immune cells), and Membrane Attack Complex (MAC) formation (direct cell lysis). Complement components are cleared from the blood by RBCs transporting C3b/C4b to the liver and spleen for phagocytosis. There are three main activation pathways leading to MAC formation: the classical, lectin, and alternative pathways.
The classical pathway is activated by an antigen-antibody complex (IgG or IgM). C1q binds to the antibody, exposing C1r and C1s proteases. These cleave C4 and C2 into C4b and C2a, which combine to form C3 convertase (C4bC2a). C3 convertase cleaves C3 into C3a and C3b. C3b joins the C3 convertase to form C5 convertase (C4bC2aC3b). C5 convertase cleaves C5 into C5a and C5b. C5b initiates the MAC by assembling C6, C7, C8, and C9 on the pathogen membrane, forming a pore and leading to cell lysis. The lectin pathway is identical to the classical pathway from C4 cleavage onwards, but it is initiated by mannan-binding lectin (MBL) from the liver forming a complex (MBL-MASP) that directly cleaves C4 and C2 without antibody involvement.
The alternative pathway is initiated by a spontaneously activated C3b molecule binding directly to a microbial surface. Factor B binds to C3b and is cleaved by Factor D into Ba and Bb. The C3bBb complex forms the alternative pathway C3 convertase. Factor P (properdin) stabilizes this C3 convertase. This stable C3bBbP complex cleaves more C3, generating more C3b. An additional C3b then joins the C3 convertase to form the alternative pathway C5 convertase (C3bBbPC3b). This C5 convertase then cleaves C5, leading to MAC formation (C5b-C9) and subsequent cell lysis, similar to the classical and lectin pathways.