lymphopoiesis

**Overview:** Lymphopoiesis is the branch of hematopoiesis producing lymphocytes. The pluripotent hematopoietic stem cell (HSC) gives rise to the multipotent progenitor, then to the common lymphoid progenitor (CLP), which is IL-7R+ and depends on transcription factors such as Ikaros (IKZF1), PU.1, and E2A. The CLP gives rise to B cells, T cells, and NK cells (and some dendritic cells). The other branch is myelopoiesis, via the common myeloid progenitor (CMP).

**B-cell lymphopoiesis (bone marrow, primary lymphoid organ):** - CLP → pro-B → pre-B → immature B → mature naive B cell. - Pro-B: TdT expressed. D-J then V-DJ heavy chain (IgH) rearrangement, which requires RAG1/RAG2. - Pre-B: surrogate light chain with μ heavy chain forms the pre-B-cell receptor, which signals through BTK. Then light chain (κ before λ) rearrangement occurs. - Immature B: surface IgM. Negative selection (central tolerance) happens in the marrow through clonal deletion, receptor editing, or anergy. - Mature naive B cell: IgM and IgD, then migrates to secondary lymphoid organs. Antigen exposure leads to germinal center reactions, class switching, somatic hypermutation (AID), and plasma or memory cell formation. - Key regulators: IL-7, EBF1, PAX5. BTK is required for pre-BCR signaling.

**T-cell lymphopoiesis (marrow → thymus):** - Thymic progenitors migrate from marrow to the thymic cortex as double-negative (CD4−CD8−) cells. - Notch1 signaling commits them to the T-cell lineage. - TCR β chain rearrangement (RAG1/2) forms the pre-TCR with pre-Tα, followed by α chain rearrangement and the double-positive (CD4+CD8+) stage. - Positive selection in the cortex: cortical epithelial cells present self-MHC. Cells that bind weakly survive and MHC I restriction yields CD8+; MHC II yields CD4+. Failure leads to death by neglect. - Negative selection in the medulla: medullary thymic epithelial cells and dendritic cells present self-antigens, with AIRE promoting expression of peripheral tissue antigens. Strong binders undergo apoptosis. Treg cells (FOXP3) also arise here. - Thymus derives from the 3rd pharyngeal pouch (endoderm = epithelium) with neural crest contributions. Thymic involution begins after puberty.

**NK cells:** Arise from the CLP in an IL-15-dependent manner. They are innate lymphoid cells (CD16+, CD56+) and do not require RAG-mediated rearrangement.

**Clinical correlations (high yield):** - **X-linked (Bruton) agammaglobulinemia:** BTK mutation causes a block at the pre-B stage. Findings: absent or very low B cells and all Ig classes, absent lymph node germinal centers/tonsils, recurrent bacterial infections after ~6 months (loss of maternal IgG), and enteroviral and Giardia susceptibility. - **SCID:** Multiple causes impair lymphopoiesis. Examples are IL-2Rγ chain mutation (X-linked, the most common form; affects common γ chain signaling for IL-2, 4, 7, 9, 15, 21), adenosine deaminase deficiency (toxic metabolites kill lymphocytes), and RAG1/2 defects (absent V(D)J recombination). Findings: failure to thrive, thrush, recurrent infections, and absent thymic shadow with low TRECs on newborn screen. - **Omenn syndrome:** Hypomorphic RAG mutations cause oligoclonal T cells, erythroderma, eosinophilia, and high IgE. - **DiGeorge (22q11.2 deletion):** Defective 3rd/4th pharyngeal pouch development causes thymic aplasia, T-cell deficiency, hypocalcemia (absent parathyroids), and cardiac defects. - **APECED / APS-1 (AIRE mutation):** Failed negative selection causes autoimmunity. - **Lymphoid malignancies:** Arrest at precursor stages causes ALL (TdT+, CD10+/CD19+ for B-ALL; T-ALL often presents with a mediastinal/thymic mass in adolescent males). t(12;21) has a good prognosis; t(9;22) has a poor prognosis. - **Lymphopenia/lymphocytosis:** Lymphopenia is seen with HIV, steroids, and DiGeorge. Reactive lymphocytosis occurs with viral infections (e.g., EBV atypical lymphocytes), and pertussis causes lymphocytosis from impaired lymphocyte homing. - **Therapeutics:** Glucocorticoids induce lymphocyte apoptosis. Cytotoxic and immunosuppressive agents such as fludarabine and cladribine are used in CLL and hairy cell leukemia. IL-7 and IL-15 are growth factors for lymphoid lineages.

**Mnemonic:** "B cells grow in Bone marrow; T cells mature in Thymus." The pre-BCR checkpoint depends on BTK. Positive selection = "MHC restriction"; negative selection = "self-tolerance."