CD45 Isoform Expression in Microglia and Inflammatory Cells in HIV‐1 Encephalitis

Abstract

CD45 is a membrane tyrosine phosphatase that modulates the function of the hematopoietic cells. In vitro, agonist antibodies to CD45RO or CD45RB isoforms have been shown to suppress microglial activation, but whether microglia in vivo express these isoforms in HIV encephalitis (HIVE) is unknown. Brain sections from control and HIVE were immunostained for CD45 isoforms using exon-specific antibodies (RA, RB, RC and RO). RA and RC were limited to rare lymphocytes, while RB expression was robust in microglia and inflammatory cells. RO was low in control microglia, but increased in HIVE. RO was also localized to macrophages and CD8+ T cells. Targeting CD45 in vivo with isoform-specific antibodies remains a therapeutic option for neuroinflammatory diseases. Pathol 2006;16:256-265. Brain INTRODUCTIONThe leukocyte common antigen (LCA: CD45) is a prototype transmembrane protein tyrosine phosphatase (PTPase) and is expressed in all nucleated hematopoietic cells (54). The CD45 protein exists as multiple isoforms as a result of alternative splicing of variable exons (4/A, 5/B and 6/C); the largest isoform (ABC) includes all three of these exons and the smallest isoform (O) lacks all three exons. Five different isoforms of CD45 (ABC, AB, BC, B and O) have been identified on human leukocytes and these can be recognized by antibodies specific to variable exons (A, B or C) or by αCD45RO (45). Although the extracellular domains differ among different isoforms, all forms share identical transmembrane and cytoplasmic domains including the phosphatase domains (52, 54).CD45 is one of the most abundantly expressed molecules in lymphocytes (comprising approximately 10% of all surface proteins) and is crucial in lymphocyte development and antigen signaling (2,12,23,54). Consequently, CD45 mutations are associated with severe combined immunodeficiency in mice and humans (5,28,51). In lymphocytes, CD45 is expressed in a cell subset-specific and activation-dependent manner. For instance, naïve T cells express a high molecular weight isoform (RA+/RO−) but upon activation switch to the smallest isoform (RA−/RO+) (16,31). At the cellular level, the CD45 phosphatase targets several families of proteins, including the Src family tyrosine kinases and Janus kinases (41), resulting in positive or negative signaling (2,4,54). In addition to lymphocytes, recent studies demonstrate that CD45 can modulate activation and proliferation of several inflammatory cell types including granulocytes, mast cells and monocytelineage cells, broadening its role as a regulator of inflammatory responses (8,20,35,48,57).In the central nervous system (CNS), microglia constitute a distinct glial cell population that is derived from hematopoietic cells in the bone marrow (17, 29, 42). As resident brain macrophages, microglia function as sentries, but when activated they can mediate tissue damage, a scenario considered for several CNS inflammatory disorders (10,15,27). In AIDS dementia and HIV encephalitis (HIVE), microglia and macrophages are productively infected by ...

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