14.1 Immunology

Microbiology Session 2 opens with host defense

/practice/nbce-part1Practice questions with detailed explanations

Quick Answer: Innate cells act in hours without clonal memory. Adaptive B and T cells rearrange receptors, then remember. CD4 sees MHC II; CD8 sees MHC I. IgM first, IgG later and across the placenta, secretory IgA at mucosa, IgE on mast cells. Complement tags (C3b), calls neutrophils (C5a), and punches holes (MAC). Live vaccines mimic infection; killed and subunit vaccines mainly raise antibody. Serology times IgM versus IgG and reports titers, ELISA, and agglutination.

Innate versus adaptive, and where the cells live

Innate immunity is present at first encounter: barriers, phagocytes, natural killer (NK) cells, complement, and inflammatory cytokines. It uses pattern-recognition receptors such as Toll-like receptors (TLRs) that bind conserved microbial motifs (lipopolysaccharide on TLR4, flagellin on TLR5, CpG DNA on TLR9, viral RNA on TLR3/7/8). Innate responses are rapid and stereotyped; they do not rearrange antigen receptors and they do not, by themselves, generate antigen-specific memory.

Adaptive immunity is clonal. Each naive B cell displays a unique membrane immunoglobulin; each naive T cell displays a unique αβ (or, less often, γδ) T-cell receptor. Encounter with antigen plus the right costimulatory context selects that clone, expands it, and leaves memory cells. Adaptive effector functions are antibody, helper cytokines, and cytotoxic killing.

Primary lymphoid organs generate the repertoire: bone marrow (B-cell development and all hematopoietic stem cells) and thymus (T-cell selection). Secondary lymphoid organs are where antigen is presented and clones expand: lymph nodes, spleen (white pulp), mucosa-associated lymphoid tissue (Peyer patches, tonsils, appendix). Lymphocyte recirculation is not trivia: a naive T cell that never enters a node will not meet its antigen. The spleen is the filter for blood-borne encapsulated bacteria; asplenic patients fail to clear Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis—the same organisms whose capsules are vaccine targets later in this section.

CD markers that items actually use: CD3 is the TCR signaling complex (all T cells). CD4 is the MHC II coreceptor. CD8 is the MHC I coreceptor. CD19/CD20 mark B cells. CD16/CD56 mark NK cells. CD14 marks monocytes. CD34 marks hematopoietic stem cells. CD40 on B cells and macrophages must bind CD40L (CD154) on activated CD4 cells or class switch and macrophage activation fail (X-linked hyper-IgM when CD40L is missing).

Antigen presentation and T-cell subsets

An immunogen elicits an adaptive response. An antigen is anything a lymphocyte receptor can bind. A hapten is a small molecule that is antigenic only after it is coupled to a carrier protein (penicillin on a red-cell protein is the teaching drug hapten). The epitope (antigenic determinant) is the patch the receptor actually contacts. T cells see linear peptide in an MHC groove; B cells can see native conformational epitopes on intact antigen.

MHC class I (HLA-A, B, C) is on all nucleated cells. It presents cytosolic peptides (viral proteins, tumor proteins) processed by the proteasome and TAP transporter. CD8 T cells read MHC I. MHC class II (HLA-DR, DP, DQ) is on professional antigen-presenting cells—dendritic cells, macrophages, B cells. It presents endocytosed peptides. CD4 T cells read MHC II. Superantigens (Staphylococcus aureus TSST-1, streptococcal pyrogenic exotoxins) glue MHC II to the TCR Vβ chain outside the peptide groove and polyclonally dump IL-2, IFN-γ, and TNF—that is immunopathology of infection, not a specific clone.

Naive CD4 cells polarize by the cytokine neighborhood:

Positive selection in thymic cortex keeps T cells that can bind self-MHC at all. Negative selection in medulla deletes high-affinity self-reactive clones (AIRE expresses tissue antigens on medullary epithelium; AIRE failure is autoimmune polyendocrine syndrome type 1). Peripheral tolerance adds anergy (signal 1 without B7–CD28 costimulation), Tregs, and activation-induced death via Fas.

CD8 effectors kill by perforin/granzyme and by FasL. They require help in the form of IL-2 and licensed dendritic cells (CD40L from CD4 cells). This is why pure antibody-raising killed vaccines are weak at clearing cytosolic viruses compared with live or vectored platforms that put antigen into the MHC I path.

Antibodies: structure, isotypes, and effector functions

A monomer immunoglobulin is two heavy and two light chains linked by disulfides. Papain cuts above the hinge into two Fab fragments (antigen binding) and one Fc (binds Fc receptors and C1q). Pepsin yields one F(ab′)2. The variable domains contain complementarity-determining regions; somatic hypermutation of those CDRs in germinal centers, plus activation-induced cytidine deaminase (AID), produces affinity maturation. Class switch also needs AID and CD40L: the same VDJ exon is joined to a different heavy-chain constant gene (μ → γ, α, or ε).

Opsonization is coating for phagocytosis: IgG and C3b are the two names to recite. Neutralization is antibody blocking toxin or viral attachment. ADCC is NK-cell CD16 binding IgG on a target. Primary response kinetics: lag of several days, IgM then IgG. Secondary (anamnestic) response: shorter lag, higher titer, mostly high-affinity IgG—the serologic signature of memory and of booster vaccination.

Complement: three routes, one C3, one MAC

Complement is a plasma proteolytic cascade that tags microbes, recruits leukocytes, and lyses some organisms (especially Neisseria).

All three pathways cleave C3. C3b covalently binds the surface (opsonin) and feeds the C5 convertase. C5b recruits C6–C9 to form the membrane-attack complex (MAC, C5b–C9), a pore. C3a and C5a are anaphylatoxins (mast-cell histamine). C5a is also a premier neutrophil chemotaxin (alongside LTB4 and IL-8 from Pathology fundamentals).

Regulators prevent self-lysis: DAF (CD55) and MCP (CD46) accelerate convertase decay; CD59 blocks MAC insertion; C1 inhibitor stops classical/lectin initiation (hereditary angioedema when it is missing—bradykinin, not histamine, dominates that edema). C3 deficiency produces severe pyogenic infections and immune-complex disease (C3b also clears complexes). MAC (C5–C9) deficiency produces recurrent Neisseria infection. C1/C2/C4 early classical deficiencies associate with SLE-like complex disease because complexes are not opsonized for spleen and liver clearance.

CH50 assays the classical pathway to MAC; a low CH50 with a normal alternative-pathway assay points upstream of C3 on the classical arm. That is serology, not a rheumatology clinic note.

Hypersensitivity and infection-linked immunopathology (keep it microbiologic)

Pathology already assigned Gell–Coombs types to named autoimmune diseases. Microbiology items more often ask which effector molecule or which lab after an infection or a vaccine.

Rheumatic fever follows untreated S. pyogenes pharyngitis, not skin infection; PSGN can follow pharynx or skin. The difference is a favorite discriminator and belongs here because it is antibody cross-reaction versus immune-complex kidney disease, not because Part I is a cardiology rotation. Guillain–Barré after Campylobacter jejuni is molecular mimicry of lipooligosaccharide and gangliosides—immunopathology of a stool pathogen. Reactive arthritis after Salmonella, Shigella, Yersinia, Campylobacter, or Chlamydia in an HLA-B27 host is another infection-triggered joint item; the organism may already be gone when the joint is hot.

Tuberculin is a type IV readout of memory Th1 cells, not proof of active cavitary disease. A negative PPD in disseminated TB can be anergy. Quantiferon-style IGRA measures IFN-γ from blood T cells stimulated with M. tuberculosis antigens that are absent from BCG, which is why IGRA is useful in BCG-vaccinated people—an immunization/serology crossover.

Immunization and vaccination

Passive immunization donates preformed antibody: maternal IgG, intramuscular immunoglobulin, monoclonal antibodies, antitoxins. Protection is immediate and temporary (weeks). Active immunization lets the host generate memory B and T cells. Protection is delayed days to weeks and is durable if memory is established.

Adjuvants (aluminum salts in many injected subunit vaccines) increase local innate activation and costimulation so the adaptive response is larger. Herd immunity is the population-level effect when enough hosts are immune that chains of transmission die out; the threshold depends on the pathogen’s basic reproduction number, which NBCE does not publish as a number you must recite—know the concept, not an invented percent.

T-independent antigens (plain polysaccharides, some repeating polymers) cross-link BCRs and yield IgM without germinal centers. Infants lack this pathway, which is why conjugate vaccines exist: the B cell internalizes the polysaccharide–protein conjugate, presents carrier peptides on MHC II, and receives CD40L/IL-21 from a carrier-specific Tfh cell. The same logic explains why asplenic adults still need pneumococcal immunization and why protein-carrier choice can theoretically interact with other protein vaccines.

Live-vaccine contraindications to recite: pregnancy, SCID and other severe T-cell defects, high-dose systemic immunosuppression. Killed and toxoid vaccines are generally usable when live vaccines are not. Egg allergy lore is over-taught; modern influenza guidance is not an NBCE fee table—if a stem still uses egg anaphylaxis, the old teaching was to avoid certain egg-grown viruses. Do not invent a 2026 CDC schedule as if NBCE printed it.

Serology: titers, ELISA, agglutination, and timing

Serology infers infection or immunity from antigen–antibody reactions in vitro. Sensitivity is the true-positive rate among the diseased; specificity is the true-negative rate among the non-diseased. A screening test (VDRL/RPR, ELISA) is built for sensitivity; a confirmatory test (FTA-ABS, Western blot in older HIV algorithms, treponemal immunoassays) is built for specificity.

A titer is the highest dilution that still reacts. Report it as a reciprocal (1:32). Seroconversion is a negative then a positive. A four-fold rise between acute and convalescent (2–4 weeks later) IgG titers is the classical proof of recent infection when IgM is unavailable or sticky. Pathogen-specific IgM suggests recent or ongoing infection but can persist or be rheumatoid-factor false-positive; IgG avidity is sometimes used to date infection (low avidity = recent).

Zone of equivalence is the ratio at which lattices form. Prozone is antibody excess (undiluted serum looks negative; dilute it and clumps appear). Postzone is antigen excess. Both are agglutination/precipitation traps.

Window period: antigen and nucleic acid can be positive before IgM. Hepatitis B teaching set (structure is in the virus section): HBsAg is the infection marker; IgM anti-HBc marks acute infection when HBsAg is present; anti-HBs alone marks vaccination; anti-HBs plus anti-HBc marks resolved infection. Heterophile-negative mononucleosis in a pregnant woman is CMV until proven otherwise; heterophile-positive is EBV. ASO titer documents prior S. pyogenes when culture is already negative (rheumatic fever workup). Cold agglutinins point to Mycoplasma pneumoniae.

PPD versus IGRA were covered as type IV assays. PCR and culture are not serology; they detect organism or nucleic acid now. A Part I stem that gives a titer without a organism smear is asking the antibody story; a stem that gives a Gram stain is asking the bacteria chapter.

Immunology on Part I is a vocabulary exam: cell, MHC, isotype, complement fragment, vaccine platform, titer interpretation. Hypersensitivity disease names are the Pathology neighbor; do not skip complement deficiencies or conjugate-vaccine logic because those sit only here.