Idiopathic CD4 Lymphocytopenia: Current Insights

Abstract

Idiopathic CD4 lymphocytopenia is a condition characterized by low CD4 counts. It is rare and most of the information about this illness comes from case reports. Presentation is usually in the 4th decade of life with opportunistic infections, autoimmune disease or neoplasia. The pathophysiology of this condition is not well understood. Management revolves around treatment of the presenting condition and close follow-up of these patients. This review presents a narrative summary of the current literature on idiopathic CD4 lymphocytopenia.

Keywords: CD4 T cell lymphocytopenia; autoimmune disease; neoplasia; opportunistic infections.

Figure 1

CD4⁺Thymocyte development. Following the migration of lymphoid precursors to the thymus, four stages of double-negative development lead to a double positive thymocyte. Loss of signalling components Lck, SLP-76, and LAT-1 results in a block at this stage of T cell development. Exposure to self-antigens presented by the cortical thymus epithelial cells (cTECs) enables positive selection. Negative selection occurs in the medulla. α, β, ε, γ, δ, and ζ denote chains of the CD3-TCR complex. Those marked with * indicate reported genetic/immunologic defects in idiopathic CD4 lymphocytopenia. Data from Zhang and Davila and Weitkamp et al. Abbreviations: CD, cluster of differentiation; SLP76, SH2-domain-containing leukocyte protein of 76 kDa; ZAP70, zeta-chain-associated protein kinase; Lck, lymphocyte-specific protein-tyrosine kinase; LAT-1, linker for activation of T cells-1; TCR, T cell receptor; NK T, natural killer T cell; Treg, regulatory T cell; DP, dual positive; DN, dual negative; SP, single positive; IL, interleukin; MHC, major histocompatibility complex; V(J)D, variable, diversity and joining regions of T cell receptor; TH, T helper cell; Costim, Costimulatory; ThPOK, T-helper-inducing POZ/Krueppel-like factor; mTEC, medullary thymic epithelial cells; VAV, guanine nucleotide exchange factor; Nur77, orphan nuclear receptor 77; S1P, sphingosine-1 phosphate; JAK3, janus kinase 3; RAG, recombination activating gene; CCL, chemokine ligand; CXCL, C-X-C motif chemokine ligand; CCR, C-C chemokine receptor.

Figure 2

T cell receptor antigen activation and signalling. Immunological synapse is formed between the antigen-presenting cell with its MHC-peptide and the TCR, CD4/8 and CD45. Activation begins with Lck activation by CD45, followed by phosphorylation of Immune-receptor-Tyrosine-based-Activation-Motif (ITAMs) and recruitment of ZAP-70 and further activation of downstream pathways that are involved in cell cycle turnover and cytoskeleton rearrangement. α, β, ε, γ, δ, and ζ denote chains of the CD3-TCR complex. Those marked by * indicate genetic defects reported in idiopathic CD4 lymphocytopenia and marked with # indicate sites of therapeutic intervention. Data from references 9, 12, 25, 30, 31, 32, 35, and 116. Abbreviations: CD, cluster of differentiation; IL, interleukin; RAG, recombination activating gene; UNC119, uncoordinated 119; Mg, magnesium; STK, serine threonine kinase; ITK, inducible tyrosine kinase; ZAP 70, zeta-chain-associated protein kinase.