Trends in Immunology
Volume 27, Issue 3, March 2006, Pages 146-153
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Altered CD45 expression and disease

https://doi.org/10.1016/j.it.2006.01.001Get rights and content

CD45, the leucocyte common antigen, is a haemopoietic cell-specific tyrosine phosphatase. Many isoforms are generated by alternative splicing, but their function remains obscure. The extracellular domain of CD45 is highly polymorphic in all vertebrates. Importantly, human polymorphic variants that alter CD45 isoform expression are associated with autoimmune and infectious diseases, establishing CD45 as an important immunomodulator with a significant influence on disease burden. Here, we discuss the new opportunities provided by the human variants for investigating and understanding how CD45 regulates antigen receptor signalling, cytokine responses and apoptosis.

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,

References (71)

  • W.P. Brooks et al.

    Effects of hemizygous CD45 expression in the autoimmune Faslgld/gld syndrome

    Cell. Immunol.

    (2001)
  • F. Esteghamat

    C77G mutation in protein tyrosine phosphatase CD45 gene and autoimmune hepatitis

    Hepatol. Res.

    (2005)
  • J. Gil

    Prevalence of C77G polymorphism in exon 4 of the CD45 gene in the Spanish population

    Med. Clin. (Barc.)

    (2005)
  • M.L. Hermiston

    CD45: A critical regulator of signaling thresholds in immune cells

    Annu. Rev. Immunol.

    (2003)
  • J.M. Penninger

    CD45: new jobs for an old acquaintance

    Nat. Immunol.

    (2001)
  • K.F. Byth

    CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation

    J. Exp. Med.

    (1996)
  • C. Kung

    Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease

    Nat. Med.

    (2000)
  • E.Z. Tchilian

    A deletion in the gene encoding the CD45 antigen in a patient with SCID

    J. Immunol.

    (2001)
  • E. Diaz del Pozo

    Genomic structure and sequence of the leukocyte common antigen (CD45) from the pufferfish Fugu rubripes and comparison with its mammalian homologue

    Immunogenetics

    (2000)
  • T. Uinuk-Ool

    Organization, alternative splicing, polymorphism, and phylogenetic position of lamprey CD45 gene

    Immunogenetics

    (2005)
  • M.F. Seldin

    Allelic variants of Ly-5 in inbred and natural populations of mice

    Immunogenetics

    (1987)
  • W.C. Raschke

    Genetic basis of antigenic differences between three alleles of Ly5 (CD45) in mice

    Immunogenetics

    (1995)
  • A. Symons et al.

    Molecular basis of antigenic differences between the RT7 alleles of rat CD45

    Immunogenetics

    (2000)
  • K.T. Ballingall

    The CD45 locus in cattle: allelic polymorphism and evidence for exceptional positive natural selection

    Immunogenetics

    (2001)
  • L.C. Filip et al.

    Rapid evolution by positive Darwinian selection in the extracellular domain of the abundant lymphocyte protein CD45 in primates

    Mol. Biol. Evol.

    (2004)
  • M. Okumura

    Comparision of CD45 extracellular domain sequences from divergent vertebrate species suggests the conservation of three fibronectin type III domains

    J. Immunol.

    (1996)
  • H. Thude

    A point mutation in the human CD45 gene associated with defective splicing of exon A

    Eur. J. Immunol.

    (1995)
  • T. Stanton

    A high-frequency polymorphism in exon 6 of the CD45 tyrosine phosphatase gene (PTPRC) resulting in altered isoform expression

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • M. Jacobsen

    A novel mutation in PTPRC interferes with splicing and alters the structure of the human CD45 molecule

    Immunogenetics

    (2002)
  • M. Jacobsen

    A point mutation in PTPRC is associated with the development of multiple sclerosis

    Nat. Genet.

    (2000)
  • T. Vyshkina

    CD45 (PTPRC) as a candidate gene in multiple sclerosis

    Mult. Scler.

    (2004)
  • L.F. Barcellos

    PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients

    Nat. Genet.

    (2001)
  • I. Vorechovsky

    Does 77C→G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus?

    Nat. Genet.

    (2001)
  • R.S. Nicholas

    The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom

    J. Neurol. Neurosurg. Psychiatry

    (2003)
  • E. Cocco

    PTPRC (CD45) C77G mutation does not contribute to multiple sclerosis susceptibility in Sardinian patients

    J. Neurol.

    (2004)
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