Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency.

PURPOSE: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. METHODS: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. RESULTS: The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. CONCLUSION: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an LMNA p.R349W Variant.

BACKGROUND: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. METHODS: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. RESULTS: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. CONCLUSIONS: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.

Photodynamic therapy with and without adjunctive intravitreal triamcinolone acetonide: a retrospective comparative study.

BACKGROUND AND OBJECTIVE: To compare photodynamic therapy (PDT) with and without adjunctive intravitreal triamcinolone acetonide (IVTA) in the treatment of choroidal neovascularization secondary to age-related macular degeneration. PATIENTS AND METHODS: Sixty-six eyes received PDT with IVTA and 73 eyes received PDT only. Outcome measures included changes in visual acuity and greatest linear dimension (GLD), the presence of angiographic leakage, the re-treatment rate, and adverse events. RESULTS: Patients treated with PDT with IVTA had reduced mean GLD compared to patients treated with PDT only at all study time points (3 [P = .0049], 6 [P = .003], and 12 [P = .05] months). Forty-four percent of patients in the PDT with IVTA group and 22% of patients in the PDT only group achieved angiographic closure at 3 months (P = .027). There were no significant differences in the final visual acuity outcome or the re-treatment rate between the two groups. CONCLUSION: PDT with IVTA therapy has a favorable outcome on GLD. There is a modest improvement in visual acuity with PDT with IVTA therapy, which diminishes over time.

Circulating inflammatory markers and hemostatic factors in age-related maculopathy: a population-based case-control study.

PURPOSE: To examine the relationship between circulating inflammatory markers, hemostatic factors, and age-related maculopathy (ARM). METHODS: A population-based, cross-sectional case-control study drawn from the Blue Mountains Eye Study included 159 early and 38 late ARM cases, and 433 controls matched for age, gender, and smoking. ARM lesions were assessed from retinal photographs according to the Wisconsin ARM grading system. Circulating inflammatory markers (high-sensitivity C-reactive protein [hsCRP], intercellular adhesion molecule [ICAM]-1, and interleukin [IL]-6), white cell count (WCC), and hemostatic factors (fibrinogen, homocysteine, plasminogen activator inhibitor [PAI]-1 and von Willebrand factor [vWF]) were assessed. Age, gender, current smoking, body mass index, hypertension, history of stroke, and cardiovascular events were adjusted for. Adjusted mean levels of each marker were compared between persons with early ARM, those with late ARM, and control subjects, and are presented as probabilities. Adjusted associations with ARM were examined continuously (per SD), and are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Summarizing z scores for inflammation and hemostatic dysfunction were calculated. RESULTS: Increased PAI-1 level was associated with both early (OR 1.2, 95% CI 1.0-1.4 per SD increase) and late ARM (OR 1.3, 95% CI 0.9-1.9 per SD increase). Elevated ICAM-1 level was marginally associated with late ARM (OR 1.3, 95% CI 1.0-1.7 per SD increase). No other significant associations were found between the remaining inflammatory or hemostatic markers and either early or late ARM. Summarized z scores for inflammatory or hemostatic markers also did not suggest any associations. CONCLUSIONS: There was no consistent pattern of association found between ARM and circulating inflammatory markers or hemostatic factors in this population-based case-control study.

Angiotensin-converting enzyme inhibitors (ACEIs) and age-related maculopathy (ARM): cross-sectional findings from the Blue Mountains Eye Study.

PURPOSE: To assess the relationship between the use of angiotensin-converting enzyme inhibitors (ACEIs) and prevalence of age-related maculopathy (ARM). METHODS: Eligible residents aged >/= 49 years were first examined in 1992-94 (Cross-section 1, n = 3654). Of these, 2335 were re-examined in 1997-99, together with an additional 1174 who became eligible after 1994 (Cross-section 2, n = 3509). Information regarding ACEI use was obtained and retinal photographs were graded using the Wisconsin ARM Grading System. RESULTS: In Cross-section 1, prevalence rates of late and early stage ARM were 1.3% and 4.3% among current ACEI users, and 2.0% and 4.8% among non-current users, respectively. In Cross-section 2, prevalence rates of late and early stage ARM were 2.3% and 11.3% among current ACEI users, and 1.3% and 9.3% among non-current users, respectively. After adjusting for age, sex and smoking, neither survey found any significant association between ACEI use and prevalence of either late or early ARM. CONCLUSIONS: No significant cross-sectional associations were found between ACEI use and ARM prevalence in this population.