How I treat monoclonal gammopathy of renal significance (MGRS).

Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.

Association of killer cell immunoglobulin-like receptors with primary Sjogren's syndrome.

OBJECTIVE: SS is a chronic inflammatory condition characterized by systemic and tissue-specific autoimmune features. In view of recent findings indicating a role for killer cell immunoglobulin-like receptors (KIRs) in the pathogenesis of other autoimmune rheumatic disorders such as SSc, and the autoimmune disorders RA and PsA, we sought to determine whether KIRs predict general or specific susceptibility in SS. METHODS: Eleven separate KIR genes were typed using PCR sequence-specific primers on genomic DNA from 72 patients diagnosed with primary SS and a control panel consisting of 223 blood donors. RESULTS: We found no individual KIR genes to be associated with SS. In contrast, 11 patients with primary SS (15%) and 9 control blood donors (4%) had KIR genotypes with the activating KIR2DS2 in the absence of its corresponding inhibitory homologue KIR2DL2 (P = 0.01). Further analysis of these individuals showed that seven SS patients were positive for HLA-C ligand for KIR2DS2 only compared with one control sample (P = 0.00026). CONCLUSION: The genetic combination of KIR2DS2+ and KIR2DL2- in the presence of HLA-C ligand specific for activating KIR2DS2 is associated with primary SS. This implies that autologous KIR-ligand interaction is a contributory factor to predisposition for this disease.

SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex.

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson's F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex.

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson's F: P=0.001). In contrast, there was a high inter - population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia.

Killer immunoglobulin-like receptors (KIRs) regulate cell activity of natural killer (NK) cells and some T cells. The predominant ligand for inhibitory KIRs is HLA-C, which subdivides into 2 groups based on the specificity of inhibitory KIRs. The ligands for activatory KIRs are unknown. Following hematopoietic stem cell transplantation (HSCT), recipient tissues may not express a ligand for KIRs present within the graft, and the combination of donor KIR and recipient HLA-C types could influence outcome. HLA and KIR genotypes were determined in 220 donor-recipient pairs from HLA-matched sibling HSCTs performed for myeloid (n = 112) and lymphoid (n = 108) diseases. In HSCTs performed for myeloid disease, overall survival was worse in patients homozygous for group 2 HLA-C (C2) than in patients who carried a group 1 HLA-C (C1) allele (P <.005). Moreover, this effect is seen only when the donor additionally carries the activating KIR gene KIR2DS2 (P =.045). No effect was seen in patients with lymphoid disease. Thus, in HLA-matched sibling HSCT for myeloid leukemia, patients homozygous for C2 alleles receiving a graft from a donor carrying the KIR gene KIR2DS2 have a significantly reduced chance of survival.

A multi-laboratory characterization of the KIR genotypes of 10th International Histocompatibility Workshop cell lines.

Killer immunoglobulinlike receptors (KIRs) are expressed on natural killer and T cells. Both inhibitory and noninhibitory forms have been described, leading to inhibition or continuation of cellular killing activity. The natural ligands identified so far of KIRs are class I human leukocyte antigens (HLA). In particular, the interaction of some KIRs with HLA-Cw has been well characterized. Recent work has implicated KIRs in affecting the outcome of hematopoietic stem-cell transplant (HSCT). This may well lead to a requirement for prospective KIR typing of donor and recipient. We have utilized different typing systems (two using polymerase chain reaction-sequence-specific primers, and one using polymerase chain reaction-sequence-specific oligonucleotide probes) in three separate laboratories to characterize the KIR gene complement of 25 cell lines from the 10th International Histocompatibility Workshop. There were consistent results in 22, and minor differences in 3. When compared with previous results for some of these cell lines, no further differences were found. The differences are due to typing of KIRs KIR2DL1 and KIR2DS5, and may be explained by technical differences or the inability to type new variants. Further improvements in typing may be required if population and clinical studies are to produce accurate results.