B-cell receptor

**Structure** - Membrane-bound immunoglobulin: 2 identical heavy chains + 2 identical light chains (kappa or lambda), joined by disulfide bonds. Each chain has a variable region (V) for antigen binding and a constant region (C). - The antigen-binding Fab portion is formed by VH + VL. The transmembrane Fc portion anchors the receptor in the membrane. - The Ig itself has a very short cytoplasmic tail and can't signal alone. It associates with the Igα/Igβ (CD79a/CD79b) heterodimer, whose cytoplasmic ITAMs (immunoreceptor tyrosine-based activation motifs) transmit the signal. - Naive mature B cells co-express surface IgM and IgD with the same antigen specificity, through alternative splicing of a long primary RNA transcript.

**Generation of diversity** - V(D)J recombination occurs in the bone marrow, mediated by RAG1/RAG2 and TdT (adds N-nucleotides). - Heavy chain rearranges first (D–J, then V–DJ), followed by light chain (V–J). Allelic exclusion ensures each B cell expresses one heavy and one light chain allele, so each cell has one specificity. - Pre-B cells express a pre-BCR: μ heavy chain + surrogate light chain (VpreB/λ5). Pre-BCR signaling drives allelic exclusion and proliferation. Btk is essential for this step. - After antigen exposure in the secondary lymphoid organs (germinal centers), AID (activation-induced cytidine deaminase) mediates: - Somatic hypermutation, which leads to affinity maturation - Class switching (IgM to IgG, IgA, or IgE), driven by T-cell help (CD40–CD40L) and cytokines. The variable region is unchanged, so antigen specificity is preserved.

**Signaling and activation** - Antigen cross-links BCRs, which phosphorylates ITAMs (Lyn, Blk, Fyn), then recruits Syk and Btk, then activates PLCγ. This produces IP3/DAG, which raises Ca²⁺ and activates PKC, NFAT, and NF-κB, leading to B-cell activation and proliferation. - The CD21 (CR2)/CD19/CD81 co-receptor complex binds C3d on antigen and lowers the activation threshold. CD21 is also the EBV receptor. - T-dependent activation: the BCR internalizes antigen, which is presented on MHC II to a helper T cell. CD40–CD40L interaction and cytokines then drive class switching and memory/plasma cell formation. - T-independent activation (for example, polysaccharides with repetitive epitopes) cross-links many BCRs and gives mainly IgM, with weak memory.

**Clinical correlations** - **X-linked (Bruton) agammaglobulinemia:** BTK mutation blocks pre-B to mature B-cell development. Findings: absent B cells (low CD19+/CD20+), low Ig of all classes, absent or small tonsils and lymph node germinal centers, and recurrent bacterial (encapsulated) and enteroviral infections after about 6 months, when maternal IgG wanes. - **Hyper-IgM syndrome:** a CD40L (T cell) or CD40 defect, or an AID defect, impairs class switching. IgM is high and other isotypes are low. - **SCID (RAG1/RAG2 mutations, Omenn syndrome):** failure of V(D)J recombination causes absent B and T cells. - **Malignancy:** B-cell clones carry one light chain type (kappa or lambda restriction), which distinguishes neoplastic from reactive proliferations. CLL/SLL, follicular lymphoma (t(14;18), BCL2 under the IgH promoter), Burkitt lymphoma (t(8;14), c-myc), and mantle cell lymphoma (t(11;14), cyclin D1) all involve Ig gene loci translocations. - **Targeted therapy:** ibrutinib, acalabrutinib, and zanubrutinib inhibit BTK (CLL, mantle cell lymphoma). Idelalisib inhibits PI3Kδ. Rituximab targets CD20, which is not part of the BCR but is a B-cell marker. - **Autoimmunity:** failure of central/peripheral tolerance (receptor editing, clonal deletion, anergy) allows autoreactive BCRs to persist.

**High-yield tolerance concept** - Immature B cells with strong self-reactivity in the bone marrow undergo receptor editing (re-rearranging the light chain), then deletion if editing fails. Weakly self-reactive cells become anergic in the periphery.

**Quick comparison** - BCR: recognizes native (conformational) antigen, no MHC restriction, and is secreted as antibody. - TCR: recognizes processed peptide on MHC, is MHC-restricted, is never secreted, and signals via CD3.