Systemic lupus erythematosus (SLE) is a highly prevalent human autoimmune diseases that causes progressive glomerulonephritis, arthritis and an erythematoid rash. Mice deficient in deoxyribonuclease I (Dnase1) develop an SLE-like syndrome. Here we describe two patients with a heterozygous nonsense mutation in exon 2 of DNASE1, decreased DNASE1 activity and an extremely high immunoglobulin G titer against nucleosomal antigens. These data are consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human SLE.

A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P ¼ 0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be B0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression. Genes and Immunity (2005) The carbohydrate recognition domain of MBL binds to high mannose and N-acetyl-glucosamine oligosaccharides on various microorganisms, while the collagen-like domain is considered to bind to its receptors on phagocytes. 1,3 MBL activates complement independently of antibodies, which is a third pathway (lectin pathway) distinct from the classical and alternative complement activation cascade. It is therefore considered that MBL is an apical and important component of innate immunity of host defense. MBL has been shown to bind to a wide range of microorganisms including fungi, bacteria, protozoa, and viruses. 4 The serum level of MBL is dependent on various factors such as polymorphisms (in the coding region) and ethnicity and age (in the promoter region). [5][6][7] Of these factors, the structural polymorphisms at codons 52, 54, and 57 in the coding region are the most important determinants. All the three polymorphisms are caused by a single amino-acid substitution and result in the profound decrease of serum MBL in the individuals carrying the polymorphisms homozygously. Two polymorphisms in the promoter region at positions À550 and À221 also have additional, but less pronounced effects on the serum level of MBL. 5 Individuals carrying either of these three codon variants homozygously are common in different ethnic groups from 5 to 10%. 4 MBL deficiency is associated with infection in infants with immature immunity, 8,9 and patients with autoimmune disorders 10 and cystic fibrosis. 11,12 An association of MBL deficiency and infection is also reported in patients treated with conventional chemotherapy 13,14 or high-dose myeloablative chemotherapy followed by allogeneic stem cell transplantation, 15 which is not confirmed by others. 16,17 In the present study, we report an increased risk of major bacterial infection in patients carrying the MBL polymorphism when treated with high-dose chemotherapy (HDT) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). In ad...

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Mannose binding lectin (MBL) deficiency may be associated with increased susceptibility to infection and autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In the present study, we performed for the first systematic search for mutations in all the four exons of the MBL gene using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. Of 49 healthy Japanese individuals studied, only the previously reported mutation at the codon 54 (substitution from Gly to Asp; G54D) was identified. The allele frequencies of G54D in 105 healthy Japanese individuals, 95 SLE patients and 59 RA patients, were 0.233, 0.226 and 0.178, respectively, which were not significantly different. In addition, two polymorhisms at positions of −550 and −221 in the promoter region were not associated with SLE and RA. It is unlikely that MBL deficiency plays a major role in the pathogenesis of SLE and RA in Japanese. Genes and Immunity (2000) 1, 464-466.Keywords: mannose binding lectin; mannose binding protein; Complement; autoimmune diseases; systemic lupus erythematosus; rheumatoid arthritis Mannose binding lectin (MBL), also known as mannose or mannan binding protein, is a member of the collectin family of proteins, characterized by the presence of collagen-like domains and carbohydrate recognition lectin domains. 1 MBL binds to high mannose and Nacetyl-glucosamine oligosaccharides present on the cell surface of yeasts, bacteria and viruses and serves as the initiator of the third pathway of complement system (lectin pathway). 2 MBL is considered to be involved in the innante immunity of host defence that works prior to the establishment of adaptive immune system. Previous studies suggest that homozygous deficiency of MBL is associated with recurrent infections in children 3,4 as well as increased susceptibility and shorter survival of human immunodeficiency virus (HIV) patients. 5,6 Although there are controversies, association of MBL deficiency with chronic hepatitis virus type B (HBV) infection 7 and its progression, 8 and with poor response to interferon in chronic hepatitis virus type C (HCV) 9 has also been reported. In addition MBL deficiency has also been implicated in the pathogenesis of autoimmune diseases. Studies in the UK and Spanish