Search

Introduction: X-linked lymphoproliferative disease is caused by mutations in two genes, SH2D1A and XIAP/BIRC4. Flow cytometric methods have been developed to detect the gene products, SAP and XIAP. However, there is no literature describing the accuracy of flow cytometric screening performed in a clinical lab setting. Methods: We reviewed the clinical flow cytometric testing results for 656 SAP and 586 XIAP samples tested during a 3-year period. Genetic testing was clinically performed as directed by the managing physician in 137 SAP (21%) and 115 XIAP (20%) samples. We included these samples for analyses of flow cytometric test accuracy. Results: SH2D1A mutations were detected in 15/137 samples. SAP expression was low in 13/15 (sensitivity 87%, CI 61–97%). Of the 122 samples with normal sequencing, SAP was normal in 109 (specificity 89%, CI 82–94%). The positive predictive values (PPVs) and the negative predictive values (NPVs) were 50% and 98%, respectively. XIAP/BIRC4 mutations were detected in 19/115 samples. XIAP expression was low in 18/19 (sensitivity 95%, CI 73–100%). Of the 96 samples with normal sequencing, 59 had normal XIAP expression (specificity 61%, CI 51–71%). The PPVs and NPVs were 33% and 98%, respectively. Receiver-operating characteristic analysis was able to improve the specificity to 75%. Conclusion: Clinical flow cytometric screening tests for SAP and XIAP deficiencies offer good sensitivity and specificity for detecting genetic mutations, and are characterized by high NPVs. We recommend these tests for patients suspected of having X-linked lymphoproliferative disease type 1 (XLP1) or XLP2. © 2014 International Clinical Cytometry Society

Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that remains difficult to treat. Even with current standard HLH therapy, only approximately half of patients will experience complete resolution of disease, and early mortality remains a significant problem. Salvage therapies have been described only in limited case reports, and there are no large studies of second-line therapies.

Fanconi anaemia is an autosomal recessive or X-linked disease characterized by progressive bone marrow failure, variable congenital abnormalities and a predisposition to malignancy. Reports of immune function in this population are limited, and include only specific areas of immune performance, showing variable defects. We report a cross-sectional immunological assessment in 10 children with FA. Absolute numbers of B cells and natural killer (NK) cells were reduced compared to controls (P = 0·048 and P = 0·0002, respectively), while absolute number of T cells were within normal range. Perforin and granzyme content of NK cells was reduced (P < 0·00001 and P = 0·0057, respectively) along with the NK cell cytotoxicity (P < 0·001). Antigen proliferation in response to tetanus was decreased (P = 0·008) while responses to candida and phytohaemagglutinin were not. Cytotoxic T cell function was also reduced (P < 0·0001). Immunoglobulin G levels were normal in those evaluated. Our series represents the first attempt at a comprehensive quantitative and functional evaluation of immune function in this rare group of patients and demonstrates a significant deficit in the NK cell compartment, a novel quantitative B cell defect, along with abnormal cytotoxic function. These findings may be especially relevant in this patient population with known predisposition to DNA damage and malignancy.

TA-TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA-TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA-TMA after allogeneic HSCT.

We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease.

Background Differences between human and murine B cells exist at all stages of B-cell development, including the stage of memory B-cell formation. B cells in mice are identified with the pan–B-cell–specific CD45 isoform, B220. In initial studies in humans, it appeared that B220 expression did not include all B cells. This study was performed to expand on those preliminary findings. Methods Multiparameter flow cytometric detection of B220 expression on B cells was combined with a variety of B-cell markers. Results In contrast to mice, B220 was not a pan–B-cell marker in humans but was downregulated in the majority of B cells that acquired the human memory B-cell marker, CD27, whereas a minor memory B-cell subset remained B220+, suggesting differences in differentiation. Conclusions The B220 isoform in humans is developmentally regulated in humans, tied to the acquisition of a memory phenotype, and as such can be used as a differentiation-specific CD45 isoform, akin to the use of CD45 isoforms to distinguish between naive and memory T-cell subsets. Patients with immunodeficiency disorders, associated with defective memory B-cell generation and absent or reduced CD27+ B cells, showed a corresponding lack of B220 downregulation consistent with altered differentiation of B-cell subsets. Cytometry Part B (Clin. Cytometry) 51B:1–8, 2003. Published 2002 Wiley-Liss, Inc.