Chapter 23: Immune Response & Lymphocyte Biology
Immune System – Core Principles & Architecture
The immune system’s primary duty: discriminate “self” vs. “non-self” to prevent infection and malignancy while avoiding auto-aggression.
Immunologic tolerance - absence of destructive antiself immune responses
Autoimmunity -failure of self vs non self discrimination, or failure of immunologic tolerance
Failure of discrimination ➜ autoimmunity; failure of tolerance induction especially critical at the B- and T-cell developmental checkpoints.
Innate vs. adaptive immunity distinctions (Table 23-1)
Innate: germ-line encoded receptors, polymorphonuclear phagocytes, NK, eosinophils; rapid non-clonal response
NK cells - principal component of innate immunity
Adaptive: rearranged antigen-specific receptors on B & T lymphocytes; clonal, delayed but specific, generates memory; mediated by the recognition of cell surface proteins encoded by major histocompatibility complex (MHC) in the short arm of chrom 6
MHC class I and MHC class II or Human leukocyte antigens (HLA class I and HLA class II)
Encodes several secreted proteins of the complement system - TNF
Non-self discrimination - adaptive immune response characterized by immunologic specificity and memory
Acquired resistance of to one antigen does not confer resistance to another unrelated (non—cross-reactive) antigen
Anamnestic or secondary immune response - cells previously exposed to and specific for one foreign protein or antigen respond more rapidly and more effectively to subsequent exposure to that same antigen
Humoral immunity - antibodies produced by B lymphocytes and their progeny
Cell-mediated immunity - mediated by T lymphocytes
Lymphocyte Ontogeny
All lymphocytes derive from CD34⁺ hematopoietic stem cells (HSCs) in fetal liver ➜ post-natal bone marrow.
CD34⁺ - gives rise to both myeloid and lymphoid early progenitors; involved in cell adhesion and important for inhibition of hematopoietic differentiation
Commitment sequences (murine & human data)
HSC ➜ Common Lymphoid Progenitor (CLP) ➜ B, T, NK; Myeloid ↔ CMP ➜ GMP / MEP.
Lineage commitment evidence: single-cell HSC division yields one repopulating HSC + one myeloid-restricted daughter (murine).
Resting B and T cells circulate in quiescent state and function only after encountering cognate antigen
Both T and B cells require costimulatory signals in the form of cell surface receptor engagement or soluble factors, for effector function
Antigen presenting cells (APCs) - accessory cells of innate immune system which mediates recognition of antigen by T cells and the costimulatory signals for both B and T cells
Each lymphocyte has only 1 specific antigen to which it can respond
T cell - unique T cell receptor (TCR); recognizes small processed oligopeptides bound within the cleft of an MHC on the surface of an APC
APC - Dendritic cells, B cells, monocytes-macrophages, epithelial Langerhans cells and endothelial cells
B cells - unique Ig displayed on the surface as B cell receptor (BCR) or be secreted
B-Cell Development (Fig 23-2 & 23-4)
B cell maturation occurs in the bone marrow -HSC committed to B lymphoid lineage develop into immature IgM+ and IgD- B cells (1st phase of B cell maturation)
Immature B cells released from the bone marrow complete their development in the spleen and differentiate into:
Follicular B cells
Marginal B cells
Most critical step - expression of Ig molecules on the surface as BCR, specificity is same as the antibody that will be secreted by the activated mature B cell progeny
Bone-marrow phases
Pro-B: CD34⁺CD19⁺CD10⁺
Pre-B: expression of \mu heavy chain + surrogate light chain (VpreB + λ5) = pre-BCR; Bruton’s tyrosine kinase (Btk) crucial; boys with Btk mutation ➜ X-linked agammaglobulinaemia - normal pro-B cells but lack pre-B cells and their progeny
Immature B: express surface IgM (sIgM) with Igα/Igβ (CD79a/b), down-regulate CD34/CD10, up-regulate CD20/CD22
sIgM+, CD19+, CD10+, and CD20+ but have not acquired IgD expression which occurs after peripheral maturation
Light-chain rearrangement: variable region of the κ gene then λ loci if κ non-productive.
Central tolerance: deletion/receptor-editing of high-affinity self-reactive clones (55-75 % of human immature B cells self-reactive).
Peripheral maturation in spleen
Naive mature B cells - resting at G0 phase, express CD19 and CD20 and sIgM
Maturation involves:
positive selection - recognize antigen
negative selection - eliminate B cells whose BCR recognize self-antigens with high affinity; deletion of potentially autoreactive clones and induction of B cell tolerance
immature B cells - CD10-, IgD+
Follicular B vs. Marginal-zone B determination influenced by BCR signal strength.
Immunoglobulin Structure (Fig 23-3)
Two 25 kDa light (κ/λ) + two 50-70 kDa heavy chains.
Variable (V), Diversity (D, heavy only), Joining (J) gene segments create V(D)J diversity; CDR3 hypervariable most diverse.
Five heavy‐chain classes: IgM, IgG (1-4), IgA (1-2), IgD, IgE – each with Fc-mediated effector functions.
Defined by expression of the heavy chain: \mu,\gamma,\alpha,\delta,\varepsilon
Ig heavy chains contain sites for binding of Fc receptors (FcR) and complement
IgM - 1st class of antibody to be produced during development
IgD - marker for later B cell deveopment
IgA - secreted as dimer, found at mucosal surfaces such as the intestine
IgG - bulk of circulating Ig
Genes encoding the heavy chains of Ig are located in chrom 14 whereas genes encoding light chains on chrom 2 and 22
Earliest B cell precursor express pan B cell marker CD19 and early marker CD10
T-Cell Development (Fig 23-5)
Differentiation occurs largely in the thymus; derived from self renewing pluripotent HSCs
Bulk of peripheral T cells - either CD4+ helper or CD8+ cytolytic lineages
CD34+ cells subdivided by expression of CD38 and MHC-like molecule CD1a
Earliest thymocytes reside in the cortex - CD34+, express pan T cell markers such as CD2 and CD7 but lack TCR-associated αβ heterodimer and CD3-associated subunits of the TCR complex and the helper and cytotoxic mature T cell coreceptors CD4 and CD8 ➜ CD3-,CD4-,CD8-, or triple negative
Thymic stages: CD3⁻CD4⁻CD8⁻ triple-negative (TN) ➜ β-selection (pre-TCR) ➜ CD4⁺CD8⁺ double positive (DP) ➜ Positive & Negative selection ➜ lineage commitment to CD4 or CD8 single-positive (SP).
CD34+, CD38-, CD1a- ➜ CD34+, CD38+, CD1a- ➜ CD34+, CD38+, CD1a+
Acquisition of CD1a - associated with loss of NK, dendritic cell and plasmacytoid dendritic cell differentiation
CD1a+ cells - express recombinase-activating gene products RAG1 and RAG2 and early TCR rearrangements detectable after acquisition of CD38 and CD1a
TCR - receptor for antigen recognition
Hallmark of cellular immune response - antigen specificity - conferred by rearranged and selected TCR on the surface of T lymphocytes
TCR gene clusters: α, β, γ, δ – serial rearrangement; TRECs from δRec-ΨJα excision serve as thymic output markers (neonatal SCID screening).
Positive selection: rescue DP that recognize self-MHC + self-peptide with low/intermediate affinity.
Negative selection: deletion of high-affinity self-reactive clones; AIRE gene in medullary TECs promotes ectopic tissue-antigen expression – mutation ➜ APECED.
Major Histocompatibility Complex (MHC)
MHC class I - major determinants are HLA-A, HLA-B and HLA-C
Ensure variation in the affinity of peptide binding; any single microbe is unlikely to mutate such that it is unable to bind all MHC molecules in the population and therefore escape T cells recognition
MHC class II - major determinants are HLA-DR, HLA-DQ and HLA-DP
Determines the affinity and specificity of peptide binding and T cell recognition; expressed only in B cells, monocyte-macrophages, and dendritic cells
May be induced on the surface of monocyte-macrophages, fibroblasts, endothelia cells, and certain mesenchymal and epidermal cells by variety of inflammatory mediators and cytokines such as IFN-γ.
Can be inducibly expressed only T lymphocytes thus rendering T cells capable of antigen presentation to other T cells
Class I (HLA-A/B/C): expressed on all nucleated cells, present 8-11 aa peptides to CD8; α chain + β2-microglobulin.
Class II (HLA-DR/DQ/DP): on APCs, present 12-20 aa peptides to CD4; αβ heterodimer.
Drug hypersensitivity (abacavir/HLA-B57:01; carbamazepine/HLA-B15:02) due to altered peptide repertoire (“p-i concept”).
Peripheral Lymphocyte Activation
B-Cell Activation
TI-1 antigens (e.g., LPS via TLRs) ➜ polyclonal IgM.
TI-2 antigens (repetitive polysaccharides) ➜ marginal-zone B; class switching aided by cytokines.
TD antigens: need cognate T cell help (CD40–CD40L, cytokines IL-4/IL-21) ➜ Germinal Center reaction: somatic hypermutation (AID-dependent), affinity maturation, class switch recombination, memory (CD27⁺) & plasma cell differentiation (CD138⁺).
BCR signaling: Igα/Igβ ITAMs phosphorylated by Lyn/Fyn/Blk ➜ Syk, BLNK, Btk, PLCγ2 ➜ DAG/IP₃ ➜ PKCβ, Ca²⁺ rise, MAPK, NF-κB, NF-AT.
T-Cell Activation
Cytotoxic Mechanisms
CD8⁺ CTL & NK: perforin/granzyme and Fas–FasL.
Defects (PRF1, UNC13D, STX11, STXBP2) ➜ Familial hemophagocytic lymphohistiocytosis.
Spleen – Anatomy & Immunologic Function
Critical secondary lymphoid organ with both immunologic and nonimmunologic function
Identified in the human embryogenesis during week 5 of gestation; weighs about 10g, then 30g at 1 year of life, 60g by 5yo
Receives 3% to 5% of the total cardiac output
White pulp - collections of lymphocytes and macrophages that form small white nodules
Periarteriolar lymphoid sheath (PALS) - circumferential ring of leukocytes that surround the central arterioles; primarily T lymphocytes;
Spheroidal lymphoid follicles - arise at intervals from PALS; primarily B lymphocytes; IgM-IgD+CD1c-CD23+
Primary follicle - naïve mature B cells that coexpress IgM and IgD; CD27-
secondary follicles - contain activated B cells within its germinal center (GC)
marginal zone - positioned around the follicles and not in direct contact with red pulp - IgM⁺IgD⁻ CD1c⁺ CD23- B cells and high levels of CD21
Marginal zone-like B cells - circulate blood with memory phenotype IgM+IgD+CD27+
Red pulp cords (Billroth) filter & groom erythrocytes; removal of inclusions (Howell-Jolly bodies) & senescent cells.
Closed (rapid) splenic circulation - erythrocytes pass directly from arterial to venous circulation by way of traditional endothelialized capillaries — primarily nutritive
Open (slow) circulation - allows careful filtration of individual erythrocytes, with repair and phagocytosis of cells that cannot successfully negotiate the return trip
Important functions:
initiates immune response for T and B lymphocyte response and proliferation
Polysaccharide antigens - require this unique immunologic environment for optimal antibody response
Intravenouse antigens - found during infection or after immunization
Early IgM response and secondary IgG response
Bloodborne bacteria, encapsulated organisms, are removed by splenic macrophages located in the PALS and in the cords
Nonimmunologic functions:
Efficient filter for erythrocytes and is able to perform grooming (removal of antibodies or other surface molecules), culling (destruction of cells), and pitting functions (removal of intracellular material)
Erythrocytes with intracellular inclusions - nuclear remnants or micronuclei (Howell-Jolly bodies), denatured hgb (Heinz bodies), siderotic granules (Pappenheimer bodies), malarial parasites
Hypersplenism - enlarged spleen trapping a larger portion of circulating blood cells
Abnormalities of the spleen:
Congenital Asplenia and Polysplenia
Ivemark Syndrome -body has bilateral right sidedness with trilobed lungs and a centralized liver; cardiac defects are common and risk of infection
Deletion of HOX11 ; heterozygous inactivating mutations in RPSA (ribosomal protein SA)
Accessory spleen and ectopic spleens
Splenosis and Splenoptosis
Wandering spleen - not fixed within the retroperitoneum; can be palpated anywhere in the abdomen
Splenosis - autotransplantation of splenic tissue into the ommentum or peritoneal surfaces of the abdominal cavity; occurs after fracture or rupture of the spleen
Splenic Sequestration
Enlargement of the spleen that occurs when blood enters the organ but is unable to exit properLy
Observed in sickle cell anemia when venous return of blood is hindered by the intrasplenic sickling or erythrocytes within the red pulp
Hypersplenism
Splenomegaly with non-immune-mediated trapping of peripheral blood cells and results in mild to moderate cytopenia
Splenectomy indications: trauma, hereditary spherocytosis, ITP/AIHA; subtotal splenectomy preserves immune function.
Overwhelming Postsplenectomy infection (OPSI) risk with encapsulated bacteria ➜ lifelong vaccination & prophylactic antibiotics.
B-Cell Activation and Function
trigger for clonal expansion of the responding B cell
Memory cells - rapidly respond on reencounter with the same antigen
Plasma cells - terminally differentiated B cells found primarily in the bone marrow specialized for high level secretion of IgG, IgM, and IgA; continuously secrete antibodies
Affinity maturation - isotype switching from low affinity IgM to high affinity IgG, IgA, or IgE and somatic hypermutation
Recognition of antigen by BCR occurs with or without T cell help
Thymus dependent (TD) - modulated and enhanced cell-cell contact with T cells
Thymus independent (TI)
Thymus-Dependent vs Thymus Independent
BCR - capable of binding a variety of antigens, including soluble proteins and polysaccharides; recognition requires cooperation with T cells, or T cell help or T cell dependent (TD);
Naive follicular B cells in lymph node follicles or the spleen recognize their cognate antigen while contacting a helper T cell specific for the same antigen
Germinal center (GC) - where isotype switching, somatic hypermutation, memory cell generation, and plasma cell differentiation occur
T1 antigens
T1-1 antigens - bacterial components that can trigger B cell activation regardless of Ig specificity and lead to polyclonal activation
Pathogen-associated molecular pattern (PAMP) - activate B cells by binding to a distinct family of receptors, TLRs accounting for their independence from Ig; ie: lipopolysaccharide (LPS)
Ig secreted in response to T1-1 is low affinity IgM because T1-1 antigen binding does not induce class switching
T1-2 antigens - molecules that have repetitive structure and activate B cells by cross-linking of multiple BCRs on a single cell leading to specific clonal antibodies production; bacterially derived polysaccharides such as in encapsulated organisms
marginal zone B cells are important for responses to T1-2 antigens
Major site - spleen; antigen produced is often IgM
Class switching does not depend on Tcell help but is enhanced by noncontact T cell factors such as IL-4
T-Cell Activation and Function
CD8+ cytolytic T cells - induce the lysis of foreign cells, such as infected, malignant, or allogeneic cells
CD4+ helper T cells - interact with B cells via cell-cell and soluble factors to induce class switching and the generation of antigen-specific antibodies; provide “help” to CD8+ cytolytic T cells
Signal 1 - TCR-MHC interaction
Signal 2 - enhance binding of variety of T cell surface molecules to their ligands on APCs
TCR αβ + CD3 ITAMs phosphorylated by Lck/Fyn ➜ ZAP-70 ➜ LAT/SLP-76 nucleation ➜ PLCγ1, Ras/MAPK, PKCθ, calcineurin–NF-AT.
Immunologic synapse (c-SMAC, p-SMAC, d-SMAC) organizes signaling; mechanotransduction via TCR–pMHC under shear (Fig 23-14).
Costimulation
Signal 2 needed to avoid anergy: CD28–CD80/86 (activation), CTLA-4 (inhibition), ICOS–ICOSL (B-cell help), PD-1–PD-L1/2 (tolerance).
TNFR family: CD40–CD40L essential for B CSR; OX40, 4-1BB, CD27 modulate survival.
TCR signaling via CD3 dimers - evokes T cell lineage commitment and repertoire selection during development, maintains the peripheral T cell pool and further differentiates naive T cells into effector or memory cell populations upon immune stimulation
Peripheral T cell Maturation
Hallmark of adaptive immunity - generation of an antigen-specific response that can be rapidly recalled upon reexposure to the same antigen at a later time
CD8+ T cell - kills targets bearing cognate antigen; suppressor cells
CD4+ T cell - produce polarized sets of effector cytokines;
T cell activation - upregulation of CD2, CD58, LFA-1, CD29, and CD44 and increase the avidity of the interaction between the T cell and the antigen-bearing APC; CD45RA expressed on naive T cells is downregulated and replaced by CD45RO isoform
Expression of CD62L (L-selectin) and CCR7
CCR7 - lymph node-homing receptor that interacts with its ligand SLC on endothelial cells
Effector memory (CCR7-) - rapidly release cytokines and kill targets
Central memory (CCR7+) - interactions with dendritic cells and B cells orchestrate effective T cell help and secondary proliferation
Helper T cell Differentiation and function
Helper subsets determined by cytokine milieu & transcription factors (Fig 23-17)
TH1: IL-12+IFN-γ/T-bet ➜ IL-12/IFN-γ/TNF-α - Cell mediated immunity: Delayed Hypersensitivity (Infection)
TH2: IL-4/GATA-3 ➜ IL-4/IL-5/IL-13. - Humoral Immunity: Immunity to parasites (allergy)
TH17: TGF-β + IL-6/RORγt ➜ IL-17, IL-22. - Mucosal immunity: Protection at mucosal sites (inflammatory disease)
Treg: TGF-β + IL-2/FOXP3 ➜ immunosuppression. - Immune regulation: Suppression of effector cells (autoimmunity)
TFH: IL-6/IL-21 + BCL6 ➜ IL-21, CXCR5. - Humoral Immunity: Activation and differentiation of B cells to antibody screening cells (humoral immunodeficiency)
Cytotoxic T cell Differentiation and Function
Effector CD8+ - primary function is direct killing of APCs infected by virus or other intracellular organism;
cytotoxicity is antigen dependent, contact dependent and does not result in destruction of the cytotoxic T cell itself
release contents of cytotoxic granules into the immune synapse after contact an infected cell
Main components:
perforin - mediate delivery of granzymes into the cytoplasm; results in congenital HLH (deficiencies in CD8 and NK cytotoxic function)
serine esterases granzyme A and granzyme B
CD95-CD95L Pathway - induction of caspase-mediated apoptosis by engagement of CD95 (Fas, Apo-1) on target cells with its ligand CD95L (Fas ligand, CD178) on effector CD8+ T cells; upregulated on activation of T cells and NK cells;control of lymphoproliferation
mutations on CD95 does not cause overwhelming infection but generalized lymphoproliferation and autoimmunity in humans - ALPS
Control of Immune response
Autoimmunity - failure of self tolerance
Central or clonal deletion - deletion by negative selection in the thymus
Anergy - encounters antigen in the absence of costimulation; inability to proliferate to a specific antigen when rechallenged while maintaining the ability to proliferate in response to cytokine
Activation-induced cell death (AICD)- ensures that the robust expansion of antigen-specific T cells is short lived and contracted
Cell-mediated suppression or regulation
Nonconventional Lymphocytes
Subset of T cells that bear αβ TCR but recognize lipid antigens rather than peptide antigens
CD1-restricted T cells - invariant NK T cells bearing Vα24-Jα18 rearranged TCRα protein
Develop on the thymus from DP stage of development
Express CD1d rather than by thymic stroma
Recognize lipid presented by CD1
α-galactosylceramide - derived from marine sponge, highly potent agonist
Produce cytokines IL-4 and IFN-γ, more rapidly than conventional TCR αβ T cells - bridge between innate and adaptive immunity in diverse processes, including response to infection, antitumor immunity, autoimmune disease, and asthma
defects ↔ sickle-cell crisis pathogenesis.
TCR γδ T cells – enriched in gut epithelium;
Most do not express either the CD4 and CD8 coreceptor
recognize non-peptidic ligands and mycobacterial antigens
NK development: bone marrow & secondary lymphoid tissue; receptors (KIR, LIR) regulate missing-self recognition
Distinct subset of lymphocytes that do not rearrange the T cell antigen receptor genes
Capacity mediate spontaneous lysis of sensitive target cells, including certain tumor cells and hematopoietic cells to mediate antibody dependent cellular cytotoxicity (ADCC)
Role in allograft rejection and tumor surveillance
Derived from common lymphoid precursor cell or directly from precursors in the bone marrow or may transit through the thymus
Clinical Correlates & Molecular Defects
SCID phenotypes (Table 24-2): impact of ADA, PNP, RAG, Artemis, CD3, IL-7R, γc/JAK3, AK2.
Agammaglobulinemia: BTK, μ heavy chain, surrogate light chain defects.
Hyper-IgM: CD40L, CD40, AID, UNG.
Autoimmunity due to impaired negative selection (AIRE) or peripheral regulation (FOXP3, CTLA-4, IL-2Rα, STAT5b).
Cytokine receptor/shared JAK-STAT defects: γc/JAK3 (multiple cytokines), IL-21R (B help), IL-17RA/F (CMC).
NF-κB pathway (NEMO, IκBα) – ectodermal dysplasia + immunodeficiency.
Complement component & regulatory protein deficiencies ➜ encapsulated bacteria, SLE-like syndromes, hereditary angioedema.
Therapeutic Highlights
HSCT: curative for SCID, WAS, CD40L deficiency, HLH.
Gene therapy successes: ADA-SCID (retroviral & lentiviral vectors), γc-SCID (insertional oncogenesis lessons).
Biologics: CTLA4-Ig (abatacept) for autoimmunity; anti-BAFF (belimumab) for SLE; cytokine blockade (tocilizumab, etanercept, etc.).
IgG replacement (IVIG/SCIG) cornerstone for humoral PIDD; antibiotic prophylaxis adjunct.
Targeted treatments: eculizumab (anti-C5) for complement-mediated HUS; kallikrein inhibitors & C1-INH concentrates for hereditary angioedema.
Ethical, Evolutionary & Translational Insights
MHC polymorphism ensures species survival vs. rapidly mutating pathogens; but predisposes to drug hypersensitivity.
Somatic gene rearrangement & SHM exemplify programmed genomic instability yielding diversity but requiring robust DNA repair (implicated in cancer & immunodeficiency).
Newborn TREC screening saves lives through early HSCT for SCID – public-health paradigm.
CAR-T therapy leverages TCR signaling knowledge for cancer immunotherapy; safety depends on co-stimulatory domain engineering.
AIRE & FOXP3 mutations illuminate checkpoints of self-tolerance, guiding therapies for autoimmunity and transplant tolerance.
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