What are the two types of adaptive immunity, and what types of microbes do these adaptive immune responses combat?
Humoral: Mediated by B cells and secreted antibodies; combats extracellular bacteria, many parasites, and soluble toxins in body fluids.
Cell‑mediated: Mediated by T cells; combats viruses, intracellular bacteria, intracellular parasites, and cancer cells by recognizing infected or abnormal host cells
What are the principal classes of lymphocytes, and how do they differ in function?
B lymphocytes: Differentiate into plasma cells that secrete antibodies and into memory B cells; key for humoral immunity.
T lymphocytes: Include CD4⁺ helper T cells that orchestrate immune responses and CD8⁺ cytotoxic T cells that kill infected or tumor cells; also form memory cells.
NK cells (innate lymphocytes): Lymphoid cells that kill virus‑infected and tumor cells without antigen‑specific receptors and provide early defense before adaptive responses.
What are the major differences between primary and secondary antibody responses to a protein antigen?
Primary response: First exposure; slower onset, lower magnitude, mainly IgM, with gradual IgG appearance and relatively lower antibody affinity.
Secondary response: Upon re‑exposure; much faster and stronger, dominated by high‑affinity IgG (and other switched isotypes), due to activation of memory B and T cells.
How does the specificity of innate immunity differ from that of adaptive immunity?
Innate immunity: Uses germline‑encoded receptors recognizing conserved patterns shared by classes of microbes (PAMPs), so the same receptor recognizes many pathogens.
Adaptive immunity: Uses somatically generated antigen receptors (BCR, TCR) highly specific for individual epitopes and capable of enormous diversity and fine discrimination, including self vs non‑self.
Which are the receptors used by the innate immune system to recognize microbial substances?
Pattern recognition receptors (PRRs) such as Toll‑like receptors (TLRs), NOD‑like receptors (NLRs), RIG‑I‑like receptors (RLRs), C‑type lectin receptors (CLRs), AIM2‑like receptors, and cGAS‑STING system.
These receptors detect microbial nucleic acids, lipids, carbohydrates, and other PAMPs, triggering inflammatory and antiviral responses.
When antigens enter through the skin, in what organs are they concentrated? What cell type(s) plays an
important role in this process of antigen capture?
Draining lymph nodes: Antigens that enter via skin are concentrated in regional lymph nodes that drain the site of entry.
Key cells: Tissue dendritic cells (especially Langerhans cells in epidermis) capture antigens, migrate via lymphatics to nodes, and present peptides to naïve T cells.
What is the function of MHC molecules?
Major histocompatibility complex (MHC) molecules bind peptide fragments of proteins and display them on the cell surface for recognition by T cell receptors.
Class I MHC presents mainly endogenous (cytosolic) peptides to CD8⁺ T cells, whereas class II MHC presents exogenous (endosomal) peptides to CD4⁺ T cells
Describe the sequence of events by which class I and class II MHC molecules acquire antigens for display.
Class I pathway (endogenous/cytosolic):
Cytosolic proteins are degraded by proteasomes into peptides.
Peptides are transported into the ER by TAP, loaded onto newly synthesized class I molecules, which then travel via Golgi to the cell surface.
Class II pathway (exogenous/endosomal):
Extracellular proteins are internalized into endosomes/lysosomes and proteolytically degraded.
Class II molecules synthesized in the ER associate with invariant chain, traffic to endosomal compartments, where invariant chain/CLIP is exchanged for peptides by HLA‑DM, and then peptide–class II complexes move to the surface.
Which subsets of T cells recognize antigens presented by class I and class II MHC molecules?
Class I MHC: Recognized by CD8⁺ cytotoxic T lymphocytes via the TCR plus CD8 coreceptor.
Class II MHC: Recognized by CD4⁺ helper T cells via the TCR plus CD4 coreceptor.
What mechanisms contribute to the diversity of antibody and TCR molecules? Which of these mechanisms contributes the most to the diversity?
Combinatorial diversity: Multiple V, D, and J gene segments recombine in different combinations for heavy/β chains and V and J for light/α chains.
Junctional diversity (most important): Imprecise joining, nucleotide addition and deletion at V(D)J junctions generates huge sequence variation, especially in CDR3.
Pairing diversity: Different combinations of heavy and light chains in antibodies, or α and β chains in TCRs, further expand specificities.
What is the phenomenon of positive selection, and what is its importance?
Thymocytes whose TCRs bind self‑peptide–MHC complexes with low to moderate affinity receive survival signals and are selected to mature.
Ensures that surviving T cells are MHC‑restricted (can recognize antigen only when presented by self‑MHC) and helps establish CD4 vs CD8 lineage commitment.
What is the phenomenon of negative selection, and what is its importance?
Thymocytes whose TCRs bind self‑peptide–MHC complexes with high affinity undergo apoptosis (clonal deletion).
Eliminates strongly self‑reactive T cells, promoting central tolerance and reducing the risk of autoimmunity.
What are the types of T lymphocyte-mediated immune reactions that eliminate microbes that are sequestered in the vesicles of phagocytes and microbes that live in the cytoplasm of infected host cells?
Microbes in phagocyte vesicles: Eliminated mainly by CD4⁺ Th1‑mediated activation of macrophages, enhancing their microbicidal functions against organisms in phagolysosomes.
Microbes in cytoplasm of host cells: Eliminated mainly by CD8⁺ cytotoxic T lymphocytes that induce death of infected cells and thus remove intracellular niches.
What are the major subsets of CD4+ effector T cells, how do they differ, and what are their roles in defense
against different types of infectious pathogens?
Th1: Induced by IL‑12/IFN‑γ; produce IFN‑γ and TNF; defend against intracellular bacteria and viruses by activating macrophages and promoting IgG opsonizing antibodies.
Th2: Induced by IL‑4; produce IL‑4, IL‑5, IL‑13; defend against helminths and promote allergic responses, eosinophil activation, and IgE production.
Th17: Induced by IL‑6, IL‑23, TGF‑β; produce IL‑17 and IL‑22; defend against extracellular bacteria and fungi at mucosal barriers, recruiting neutrophils.
Tfh (T follicular helper): Localize in germinal centers, provide help to B cells for isotype switching and affinity maturation via cytokines such as IL‑21.
Treg (regulatory T cells): Induced by or express FOXP3; produce IL‑10 and TGF‑β; suppress excessive immune responses and maintain tolerance.
What are the mechanisms by which T cells activate macrophages, and what are the responses of
macrophages that result in the killing of ingested microbes?
T cell mechanisms:
CD40L on activated Th1 cells engages CD40 on macrophages, and IFN‑γ from Th1 cells provides a strong activating signal.
Additional cytokines such as TNF and GM‑CSF can augment activation and survival.
Macrophage responses:
Upregulation of reactive oxygen species, inducible nitric oxide synthase (NO production), and lysosomal enzymes to kill ingested microbes.
Increased expression of MHC and costimulators, and secretion of inflammatory cytokines that enhance further T cell and innate responses.
How do CD8+ CTLs kill cells infected with viruses?
Granule exocytosis pathway: CTLs release perforin to form pores in target cell membranes and granzymes that enter and trigger caspase‑dependent apoptosis.
Death receptor pathway: CTLs express Fas ligand (FasL) which engages Fas on target cells, activating the apoptotic cascade; both mechanisms kill infected cells without massive bystander damage.
How are antigens transported from the gut lumen to the lamina propria?
M cells in the follicle-associated epithelium of Peyer’s patches and villi take up particulate antigens and microbes by endocytosis and transcytose them to dendritic cells and B cells beneath.
Dendritic cells can extend transepithelial dendrites between epithelial cells to sample luminal antigens and then migrate to mesenteric lymph nodes.
Which mechanisms are involved in the regulation of innate immune responses in the intestinal mucosa?
Epithelial and mucus barrier: Tight junctions, mucus layers, and antimicrobial peptides limit microbial contact and dampen unnecessary PRR signaling.
Regulatory immune cells and cytokines: Tregs, tolerogenic dendritic cells, and regulatory macrophages produce IL‑10, TGF‑β and other mediators that restrain inflammation.
Microbiota-dependent signaling: Commensal-derived signals condition epithelial and innate cells to maintain a balanced, hyporesponsive but alert state.
How are gut homing properties imprinted in intestinal lymphocytes?
Site of imprinting: Dendritic cells in Peyer’s patches and mesenteric lymph nodes metabolize vitamin A into retinoic acid, which acts on activated T and B cells.
Homing receptors induced: Retinoic acid and local cytokines induce expression of integrin α4β7 and chemokine receptor CCR9 (and CCR10), directing lymphocyte migration to intestinal lamina propria and epithelium.
Explain how IgA is produced in the gut.
Induction sites: Peyer’s patches, isolated lymphoid follicles, and mesenteric lymph nodes initiate IgA class switching in B cells.
T cell–dependent pathway: Tfh cells provide CD40L and cytokines (notably TGF‑β1, plus IL‑21 and others), driving class-switch recombination to IgA and formation of high-affinity, somatically mutated IgA.
T cell–independent pathway: Microbial products and innate signals (e.g., BAFF, APRIL) stimulate IgA switching outside classical follicles, generating more polyreactive IgA.
Effector cells: Switched B cells home to lamina propria and differentiate into IgA‑secreting plasma cells.
There are antibodies present in the gut lumen, despite being produced in the lamina propria (on the other
side of the epithelial layer). How is this possible?
Polymeric IgA production: Lamina propria plasma cells secrete dimeric IgA bound by the J chain.
Transcytosis via pIgR: Epithelial cells express the polymeric immunoglobulin receptor (pIgR), which binds dimeric IgA basolaterally, transports it across the cell, and releases secretory IgA (sIgA) into the lumen with the attached secretory component that protects it from proteolysis.
Explain how gut homeostasis is maintained.
Physical and chemical barriers: Intact epithelium, mucus, and antimicrobial peptides limit microbial penetration while allowing nutrient absorption.
Immune tolerance to commensals and food: Tregs, tolerogenic DCs, and IgA responses promote non‑inflammatory containment of microbiota and food antigens (oral tolerance).
Balanced microbiota–host interactions: Commensals help educate the immune system, while IgA and innate effectors shape microbial composition to avoid overgrowth of pathobionts.
Explain the underlying basis of celiac disease as well as Inflammatory bowel disease.
Celiac disease:
In genetically susceptible individuals (HLA‑DQ2 or HLA‑DQ8), gluten‑derived gliadin peptides cross the epithelium, are deamidated by tissue transglutaminase (TG2), and presented by HLA‑DQ2/8 to CD4⁺ T cells.
This drives a Th1/Th17‑skewed response with IFN‑γ and other cytokines, activation of cytotoxic intraepithelial lymphocytes, anti‑TG2 and anti‑gliadin antibodies, and villous atrophy.
Inflammatory bowel disease (IBD: Crohn’s disease and ulcerative colitis):
Caused by a dysregulated immune response to intestinal microbiota in genetically susceptible hosts, involving defects in barrier function, innate sensing, autophagy, and regulatory pathways.
Excessive activation of effector T cells (e.g., Th1/Th17 in Crohn’s), impaired Paneth cell function, and altered microbiota composition contribute to chronic mucosal inflammation and tissue damage.
Which are the requirements for memory T cell survival?
IL-7 acts as the primary homeostatic cytokine for both CD4⁺ and CD8⁺ memory T cells, driving survival and slow proliferation; IL-15 provides complementary support, especially for CD8⁺ subsets.
