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Introduction
T-bet(high) CD21(low) B Cells in CVID
CVID, Inflammatory Pathways and Immune Dysregulation
CVID: Treatment of Inflammatory Complications
AUTOIMMUNE CYTOPENIAS AND INTERSTITIAL LUNG DISEASE ARE ASSOCIATED WITH EXPANDED TH1 CELLS IN LOCID AND CVID PATIENTS
Abstract
Background and Aims
Several alterations of CD4T subsets have been reported in CVID patients, although most studies did not discriminate patients with an underlying defect in CD4T cell production fulfilling late onset combined immunodeficiency criteria (LOCID).
Methods
CD4T subsets were analyzed in 49 CVID and 20 LOCID patients, in parallel with 155 healthy donors (4-88 years) using EuroFlow-based flow cytometry methods
Results
Higher percentage of patients with decreased T-cell subset counts were observed in LOCID vs. CVID, including Treg (85% vs. 61% of patients), Th2 (95% vs. 47%), Th17 (90% vs. 47%), and Th1/Th2 (65% vs. 29%), as compared to age-reference values. In contrast, few LOCID and CVID patients showed decreased TFH (5% and 2%), Th1 (25% and 18%), and Th1/Th17 counts (15% and 12%). Multivariate analysis showed two clearly distinct subgroups of LOCID, those with higher Th1 counts presenting with a higher frequency of autoimmune cytopenia (89% vs 19%, p=0.003) and interstitial lung disease (78% vs. 9%, p=0.003), together with lower frequency of non-respiratory infections (57% vs. 100%, p=0.03). In addition, three CVID subgroups were identified based on Th1 and TFH cells (CVID1, CVID2, and CVID3) with a significantly higher frequency of autoimmune cytopenias in CVID cases with higher Th1 cells (63% vs. 8% vs. 22%, p=0.005).
Conclusions
LOCID patients presented with a deeper T-cell defect than CVID patients. Interestingly, increased Th1 counts strongly associates with the presence of autoimmune cytopenia in LOCID and CVID; this coincides with interstitial lung disease in LOCID patients, but not in CVID.
MAP KINASE ACTIVATING DEATH DOMAIN (MADD) DEFICIENCY IS A NOVEL CAUSE OF IMPAIRED LYMPHOCYTE CYTOTOXICITY
Abstract
Background and Aims
Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome 2 (GS2, RAB27A deficiency). Deficiency of the mitogen activated protein (MAP) kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine-nucleotide exchange factor for small GTPases, including RAB27A.
Methods
A female infant with syndromal features, secretory diarrhea, and features of HLH underwent routine exome sequencing. Degranulation and cytotoxicity of cytotoxic cells and platelet secretion were analyzed. To prove the relationship between the detected MADD defect and the detected functional impairment, we performed the assays in an NK-92mi cell line, in which we had introduced a CRISPR/Cas9 based MADD knock-out. A second MADD deficient patient was analyzed for confirmation.
Results
A homozygous splice site mutation in MADD was identified. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 bp and favors other aberrant variants. Patient NK cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective ATP secretion, comparable to GS2. MADD deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another the second MADD deficient patient.
Conclusions
In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect, most likely due to impaired RAB27a activation, and represents a novel disease predisposing to an HLH phenotype.