The Exon A (C77G) Mutation Is a Common Cause of Abnormal CD45 Splicing in Humans

Tchilian, Elma; Wallace, Diana L.; Imami, Nesrina; Liao, Hua‐Xin; Burton, Catherine; Gotch, Frances; Martinson, Jeremy; Haynes, Barton F.; Beverley, Peter C. L.

doi:10.4049/jimmunol.166.10.6144

Cited by 20 publications

(21 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The G77G homozygote shown in Fig. 2 was an anonymous thymic specimen from a patient undergoing cardiac surgery [33,34], so we have no information on the CD45RA/R0 phenotype of homozygous peripheral blood lymphocytes. Nor, although there are several syndromes associating cardiac and immunological abnormalities [35,36], do we have any information on the clinical status of the patient, as we could not obtain this for ethical reasons.…”

Section: Discussionmentioning

confidence: 99%

Unusual case presentations associated with the CD45 C77G polymorphism

Tchilian

Gil

Navarro

et al. 2006

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryCD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases.

show abstract

Section: Discussionmentioning

confidence: 99%

Unusual case presentations associated with the CD45 C77G polymorphism

Tchilian

Gil

Navarro

et al. 2006

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…This mutation, found in approximately 1:60 of the UK population, results in an inability to generate low molecular weight isoforms of the CD45 molecule encoded by that allele [17]. Hence, subject 1 had no single-positive CD45R0…”

Section: Lymphocyte Phenotypementioning

confidence: 99%

Rapid turnover of T cells in acute infectious mononucleosis

et al. 2003

View full text Add to dashboard Cite

During acute infectious mononucleosis (AIM), large clones of Epstein-Barr virus-specific T lymphocytes are produced. To investigate the dynamics of clonal expansion, we measured cell proliferation during AIM using deuterated glucose to label DNA of dividing cells in vivo, analyzing cells according to CD4, CD8 and CD45 phenotype. The proportion of labeled CD8 + CD45R0 + T lymphocytes was dramatically increased in AIM subjects compared to controls (mean 17.5 versus 2.8%/day; p X 0.005), indicating very rapid proliferation. Labeling was also increased in CD4 + CD45R0+ cells (7.1 versus 2.1%/day; p X 0.01), but less so in CD45RA + cells. Mathematical modeling, accounting for death of labeled cells and changing pool sizes, gave estimated proliferation rates in CD8 + CD45R0 + cells of 11-130% of cells proliferating per day (mean 47%/day), equivalent to a doubling time of 1.5 days and an appearance rate in blood of about 5×10 9 cells/day (versus 7×10 7 cells/day in controls). Very rapid death rates were also observed amongst labeled cells (range 28-124, mean 57%/day), indicating very short survival times in the circulation. Thus, we have shown direct evidence for massive proliferation of CD8 + CD45R0 + T lymphocytes in AIM and demonstrated that rapid cell division continues concurrently with greatly accelerated rates of cell disappearance.

show abstract

“…We obtained material from two patients with HLH, previously described as exhibiting CD45 abnormal splicing, as characterized by the lack of the single CD45R0ϩ T cell population (22,23). Subsequently the C77G mutation in exon A of CD45 has been shown to be a common cause for abnormal CD45 splicing in T lymphocytes (10,34). We therefore re-examined these patients and members of their families to establish the cause for abnormal CD45 splicing.…”

Section: Resultsmentioning

confidence: 99%

“…Genomic DNA was amplified by PCR using forward (5'-GACTACAG-479 CD45 ABNORMAL SPLICING CAAAGATGCCCAGTG-3') and reverse (5'-GGGATACTT-GGGTGGAAGTA-3') primers as previously described (34). The PCR and digestion products were analyzed on VisiGel Separation Matrix (Stratagene, La Jolla, CA, U.S.A.).…”

Section: Patientsmentioning

confidence: 99%

“…PBMC were stimulated for 12 d with 1g/mL of PHA-P (Sigma Chemical Co., St. Louis, MO, U.S.A.) adding IL-2 on day 10. Flow cytometric analysis of CD45 variant splicing was performed as previously described (34). Briefly, 2ϫ10 5 PBMC were stained with either APCconjugated CD4 (S3.3, Caltag, Siulverstone, UK) or CD8-APC (clone RPA/T8, Pharmingen, San Diego, CA, U.S.A.) along with FITC-conjugated CD45RA (clone HI10, Pharmingen) and PE-conjugated CD45R0 (clone UCHL1, Pharmingen) mAbs in a single step at 4°C for 20 min and washed with PBS, containing 0.2% BSA.…”

Section: Patientsmentioning

confidence: 99%

See 1 more Smart Citation

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

et al. 2004

View full text Add to dashboard Cite

Hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH) are members of a group of rare heterogenous disorders, the histiocytoses, characterized by uncontrolled accumulation of pleomorphic infiltrates of leukocytes. The etiology of these diseases is mainly unknown. CD45 is a hemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signaling in lymphocytes and different patterns of CD45 splicing are associated with distinct functions. Recently a polymorphism (C77G) in exon 4 of CD45 causing abnormal CD45 splicing and a point mutation affecting CD45 dimerization were implicated in multiple sclerosis in humans and lymphoproliferation and autoimmunity in mice respectively. Here we show that two patients with HLH exhibited abnormal CD45 splicing caused by the C77G variant allele, while a further 21 HLH patients have normal CD45. We have also examined 62 LCH patients and found three to have the C77G mutation. Peripheral blood thymus-derived (T) CD8ϩ cells from normal individuals carrying the C77G mutation show a significant decrease in the proportion of cells expressing L-selectin and increased frequency of cells with LFA-1 hi expression. It remains to be established whether C77G is a contributing factor in these histiocytic disorders. The leukocyte common antigen CD45 is an abundant tyrosine phosphatase, essential for lymphocyte antigen receptor signal transduction (1). Both CD45 knockout mice (2, 3) and humans lacking CD45 expression (4, 5) are severely immunodeficient with very few peripheral T lymphocytes and impaired T and B cell responses.Multiple CD45 isoforms can be generated by alternative splicing of exons A, B, and C of the extracellular domain (6, 7). In humans naïve T cells express high molecular weight CD45 isoforms, recognized by CD45RA MAb ("CD45RA" cells), but activation of the cells results in a change to expression of low molecular weight isoforms, detected by a CD45R0 MAb ("CD45R0" or memory cells) (8). Paragraph deleted. Several polymorphisms of the gene encoding CD45 (PTPRC at 1q31-32) have been described and several of these cause altered splicing (9 -14).The C77G polymorphism (9 -12) has been linked to the development of multiple sclerosis in German (15)

show abstract

The Exon A (C77G) Mutation Is a Common Cause of Abnormal CD45 Splicing in Humans

Cited by 20 publications

References 27 publications

Unusual case presentations associated with the CD45 C77G polymorphism

Unusual case presentations associated with the CD45 C77G polymorphism

Rapid turnover of T cells in acute infectious mononucleosis

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

Contact Info

Product

Resources

About