Trends in Immunology
Altered CD45 expression and disease
Section snippets
The puzzle of CD45
The CD45 (leucocyte common) antigen is a haemopoietic cell-specific tyrosine phosphatase essential for efficient T and B cell antigen receptor signal transduction 1, 2. Multiple CD45 isoforms can be generated by complex alternative splicing of exons 4 (A), 5 (B) and 6 (C), in the extracellular domain of the molecule (Figure 1). The expression of different CD45 isoforms is cell type-specific and dependent on the stage of differentiation and state of activation of cells. In humans, naive T
CD45 allelic variants in non-human vertebrates
CD45 genes from many vertebrate species have been sequenced. In lampreys and the puffer fish, extensive polymorphism has been documented 6, 7. Three alleles, Ly5a, Ly5b and Ly5c, have been identified in inbred strains of mice and at least eight additional alleles in wild mice [8]. Although two silent changes were found in the cytoplasmic domain, most of the sequence changes are in the constant part of the extracellular domain [9]. In rats, the two alleles RT7a and RT7b produce four amino acid
Human exon 4 variants
The most extensively studied human CD45 polymorphism is the C77G point mutation in a splice silencer region of exon 4, which prevents excision of the exon [18]. Consequently, memory/effector lymphocytes of C77G carriers express CD45RA and CD45RO instead of the normal pattern of low molecular weight CD45RO expression. C77G heterozygous individuals are relatively rare (allele frequency 0–3.5%; Table 1), although the allele frequency is 6.7% in a highly endogamous population in the Pamir
The human exon 6 A138G polymorphism
The exon 6 A138G allele is found at a frequency of ∼20% in Japanese samples, with nearly 5% of individuals homozygous for the G allele, and is the first common CD45 polymorphism to be described [15] (Table 1). The allele is present at a similar frequency in China, Thailand, Cambodia, Vietnam and Peru and at a frequency of ∼9% in India (V. Ward, B. Hennig, W.F. Bodmer, A.V. Hill, P.C.L. Beverley and E.Z. Tchilian, unpublished). The A138G transversion results in an amino acid substitution of
Genetic modifiers and CD45
Altered CD45 expression might not always be caused by polymorphisms in the CD45 locus, but could be influenced by molecules encoded by other genes (genetic modifiers) such as splice factors, transcription factors and others. For example, the SR (serine, arginine rich) family of splice factors have antagonistic affects on CD45 splicing, leading to inclusion or skipping of exons A, B and C in co-transfection experiments [39]. Consensus sequence motifs within the variable exons have been defined
Mechanisms of CD45 action in disease
How does altered CD45 regulate immune function and disease? At least three mechanisms can be proposed (Figure 3). The first is by controlling the threshold of signalling through the TCR. The crucial role of CD45 phosphatase activity for T and B cell receptor signal transduction is well established, and SRC family kinases are its primary targets (reviewed in 1, 2, 45). Thus CD45 dephosphorylates the negative regulatory site of LCK, the tyrosine residue at position 505, leading to LCK activation,
The function of CD45 isoforms
Although alterations in CD45 isoform expression strongly influence lymphocyte function, the function of individual isoforms remains obscure. No specific ligand has been found for CD45, although interactions with lectin-like molecules have been reported. However, a large CD45 extracellular domain is required for normal T cell receptor signalling in transfected cell lines [56]. The formation of homodimers and heterodimers by CD45 isoforms has been proposed as another mechanism that might regulate
Conclusions and future perspectives
Here, we have described recent evidence showing that CD45 is highly polymorphic in several species. In humans, two variants with contrasting phenotype, geographical distribution and disease associations have been described. These results support the view that the pattern of CD45 isoform expression is important for immune function, and we propose that the effects of altered CD45 expression on disease might be mediated by alterations in the threshold of lymphocyte antigen receptor triggering,
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2022, Cell ReportsCitation Excerpt :Expression of distinct CD45 isoforms serves an important function in the immune system. Patients carrying mutations resulting in impaired CD45 splicing exhibit an altered T cell phenotype ratio and increased susceptibility to autoimmune and infectious diseases (Tchilian and Beverley, 2006; Tchilian et al., 2001; Vogel et al., 2003). Moreover, genetically altering the combination of isoforms expressed by T cells has been shown to increase the onset and severity of autoimmunity (Dawes et al., 2006).
Urinary mRNA analysis of biomarkers to epithelial mesenchymal transition of renal allograft
2018, Nephrologie et TherapeutiqueCD45 in human physiology and clinical medicine
2018, Immunology LettersCitation Excerpt :GCS-100, a galectin-3 inhibitor used in experiments by Clark et al. [158]{h}, was assessed in several studies, but no clinical trial has reached phase III yet, for unknown reasons. CD45, being an important regulator of immune cell signaling pathways, has been linked to several diseases [207,208] and thus, therapeutic modulation of CD45 function has direct clinical applicability in organ transplantation, treatment of autoimmune disease or microglial activation associated with Alzheimer disease (AD). As a matter of fact, CD45 was one of the first protein tyrosine phosphatases to be considered as a drug target.
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