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Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and/or a defective antibody response to T-dependent and T-independent antigens. CVID response to immunization depends on the antigen type, the vaccine mechanism, and the specific patient immune defect. In CVID patients, humoral and cellular responses to the currently used COVID-19 vaccines remain unexplored. Eighteen CVID subjects receiving 2-dose anti-SARS-CoV-2 vaccines were prospectively studied. S1-antibodies and S1-specific IFN-γ T cell response were determined by ELISA and FluoroSpot, respectively. The immune response was measured before the administration and after each dose of the vaccine, and it was compared to the response of 50 healthy controls (HC). The development of humoral and cellular responses was slower in CVID patients compared with HC. After completing vaccination, 83% of CVID patients had S1-specific antibodies and 83% had S1-specific T cells compared with 100% and 98% of HC (p = 0.014 and p = 0.062, respectively), but neutralizing antibodies were detected only in 50% of the patients. The strength of both humoral and cellular responses was significantly lower in CVID compared with HC, after the first and second doses of the vaccine. Absent or discordant humoral and cellular responses were associated with previous history of autoimmunity and/or lymphoproliferation. Among the three patients lacking humoral response, two had received recent therapy with anti-B cell antibodies. Further studies are needed to understand if the response to COVID-19 vaccination in CVID patients is protective enough. The 2-dose vaccine schedule and possibly a third dose might be especially necessary to achieve full immune response in these patients.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2],P=2.1×10−4). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years;P=1.68×10−5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Background: COVID-19 clinical features include a hypercoagulable state that resembles the antiphospholipid syndrome (APS), a disease characterized by thrombosis and presence of antiphospholipid antibodies (aPL). The relationship between aPL-presence and the appearance of thrombi as well as the transience or permanence of aPL in COVID-19 patients is not sufficiently clear. Methods: A group of 360 COVID-19 patients were followed-up for 6 months. Classic aPL, anti-B2GPI IgA, anti-phosphatidylserine/prothrombin IgG/M and anti-SARS-CoV-2 antibodies were determined at acute phase and &gt, 12 weeks later. The reference group included 143 healthy volunteers of the same age-range distribution. Results: aPL prevalence was similar in COVID-19 patients and the reference population. aPL presence in both determinations was significantly associated with thrombosis (OR: 2.33 and 3.71), strong agreement being found for classic aPL and anti-B2GPI IgA (Weighted kappa: 0.85–0.91). Thrombosis-associated aPL occurred a median of 17 days after hospital admission (IQR: 6–28) vs. 4 days for the rest (IQR: 3–7). Although anti-SARS-CoV-2 antibodies levels increased during convalescence, aPL hardly changed. Conclusions: Most COVID-19 patients would carry these aPL before the infection. At least two mechanisms could be behind thrombosis, early immune-dysregulation-mediated thrombosis after infection and belated-aPL-mediated thrombosis, with SARS-CoV-2 behaving as a second hit.

Recurrent pregnancy loss (RPL) affects up to 6% of couples. Although chromosomal aberrations of the embryos are considered the leading cause, 50% of cases remain unexplained. Antiphospholipid Syndrome is a known cause in a few cases. Antiphospholipid antibodies (aPL) anticardiolipin, anti-Beta-2-Glycoprotein-I and Lupus Anticoagulant (criteria aPL) are recommended studies in RPL workup. We tested healthy women with unexplained RPL for criteria aPL and anti-Phosphatidylserine/Prothrombin antibodies (aPS/PT). Patients were classified into three groups according to the number and pregnancy week of RPL: Extra-Criteria (EC), with 2 miscarriages, Early Miscarriage (EM), with ≥3 before pregnancy at week 10 and Fetal Loss (FL), with ≥1 fetal death from pregnancy at week 10. Circulating criteria aPL were absent in 98.1% of EM, 90.9% of FL and 96.6% of EC groups. In contrast, aPS/PT were positive in 15.4% of EM, 15.1% of FL, 16.6% of EC patients and 2.9% in controls. aPS/PT posed a risk for RPL, with an odds ratio of 5.96 (95% confidence interval (CI): 1.85–19.13. p = 0.002) for EM, 7.28 (95% CI: 2.07–25.56. p = 0.002) for FL and 6.56. (95% CI: 1.77–24.29. p = 0.004) for EC. A successful live birth was achieved in all pregnant patients positive for aPS/PT who received treatment with heparin, aspirin and/or hydroxychloroquine.

IntroductionMonoclonal antibodies (mAb) targeting plasma cells are malignant gammopathy designed and approved therapies. In recent years, these antibodies have also been increasingly introduced for non-malignant conditions such as autoimmune-mediated diseases. The Anti-Phospholipid Syndrome (APS) is an immune-mediated disorder in which autoantibodies against phospholipid associated proteins could elicit the activation of the coagulation cascade in specific situations. Therefore, the mainstream treatment for APS patients is the use of anticoagulant therapy. However, there are refractory patients who would benefit from targeting the antibodies rather than their effects. Rituximab, a B-cell depleting mAb, and intravenous immunoglobulins (IVIG) have been used in APS patients without showing a clear beneficial effect or a significant drop in anti-phospholipid antibody (aPL) levels.Clinical caseWe present our first APS case treated with daratumumab, an anti-CD38 mAb, in a 21-year-old patient with APS who presented with recurrent venous thromboembolic events despite adequate anticoagulant therapy. She tested positive for lupus anticoagulant, anti-cardiolipin IgG, anti-beta-2-glycoprotein-I IgG and anti-phosphatidylserine/prothrombin IgG and IgM. She was administered one dose weekly of daratumumab for 4 weeks. The treatment showed an adequate safety profile and was well tolerated. The patient was discharged after undergoing a clinically significant improvement. After the therapy, her levels of positive aPL declined significantly and most continued to decrease during the next three months. The patient experienced a new thrombotic episode two years after the therapy associated with poor adherence to antithrombotic therapy.ConclusionsThe treatment with daratumumab showed an adequate safety profile, was well tolerated and led to a significant clinical improvement. Levels of aPL lowered on therapy and the next three months and then rose again during follow-up. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in treatment of refractory APS.

Background: Antiphospholipid syndrome is characterized by recurrent thrombosis and gestational morbidity in patients with antiphospholipid autoantibodies (aPLs). Predictive value of the presence of aPLs is low, and new markers are necessary to identify aPL carriers at higher risk and take preventive measures on them. The presence of circulating immune complexes of IgA bound to β 2 -glycoprotein I (B2A-CIC) has been associated with occurrence of acute thrombotic events. In this work we study its possible predictive value for the appearance of acute thrombotic events in patients who are going to undergo transplant surgery, a well-known trigger of acute thrombotic events in aPL carriers. Methods: We performed a follow-up study based on the Magnum 12+12 Cohort of patients who received a kidney transplant (n=1339). Three groups were established: group 1 patients who were positive for IgA anti-β 2 -glycoprotein I (aB2GP1) and B2A-CIC (n=125); group 2 patients who were positive only for IgA aB2GP1 (n=240); and control group, patients who were negative for IgA aB2GP1 (n=974). Levels of autoantibodies and B2A-CIC were quantified immediately before the transplant surgery and patients were followed up for 6 months. Results: In group 1, 46.4% of patients experienced any type of thrombosis versus 10.4% in group 2 ( P P P P Conclusions: The presence of B2A-CIC is a predictor of acute thrombotic events. Patients who were positive for IgA aB2GP1 only are at risk of experiencing thrombosis if they are B2A-CIC positive. If they are B2A-CIC–negative patients, they have the same risk as the control group. Treatments to prevent acute thrombotic events should focus on B2A-CIC–positive patients.

In transplanted intestines, depletion of T cells together with long-term persistence of ILC is observed, suggesting ILC insensitivity to immunosuppressive drugs. To further analyze helper ILC (hILC) apparent resistance to therapy, cytotoxic ILC (NK cells), hILC subsets (ILC1, ILC2, and ILC precursors (ILCP)), and their signature cytokines (IFNγ, IL4 + IL13, and IL22) were analyzed in peripheral blood of kidney and liver transplant recipients. Early after transplantation (posTx), transplanted patients showed significantly lower Lin + and NK cells, whereas total hILC, ILC1, ILC2, and ILCP numbers were similar in patients and controls. Between paired pre- and posTx samples, Lin + cell and NK cell counts significantly decreased, whereas all three hILC counts and their cytokine production remained similar. ILC1, ILC2, and ILCP numbers were also similar in patients under thymoglobulin or basiliximab (BAS), patients without induction (only maintenance therapy) and controls. hILC showed lower TMG binding comparing to Lin + cells, reduced expression of CD25 (BAS target), and diminished calcineurin activity with undetectable calcineurin and FKBP12 (tacrolimus target). hILC counts were not related to delayed graft function or biopsy-proven acute rejection. Thus, hILC remain stable early after transplantation and seem unaffected by immunosuppressors, which may be related to reduced targets expression and low calcineurin activity.

The specific value of IgA Anti-β2glycoprotein I antibodies (aB2GP1) in the diagnosis and management of antiphospholipid syndrome (APS) is still controversial and a matter of active debate. The relevance of the IgA aB2GP1 isotype in the pathophysiology of APS has been increasingly studied in the last years. There is well know that subjects with multiple positive APS tests are at increased risk of thrombosis and/or miscarriage. However, these antibodies are not included in the 2006 APS classification criteria. Since 2010 the task force of the Galveston International Congress on APS recommends testing IgA aB2GP1 isotype in patients with APS clinical criteria in the absence of criteria antibodies. In this review, we summarize the molecular and clinical “state of the art” of the IgA aB2GP in the context of APS. We also discuss some of the characteristics that may help to evaluate the real value of the IgA aB2GP1 determination in basic research and clinical practice. The scientific community should be aware of the importance of clarifying the role of IgA aB2GP1 in the APS diagnosis.

Selective IgA deficiency (SIgAD) is the most prevalent immunodeficiency worldwide, progressing to common variable immunodeficiency only in few reported cases. We report the case of a Spanish female aged 22 and diagnosed of selective IgA deficiency, a long history of bronchitis, several episodes of pneumonia, bilateral bronchiectasis, normal IgG, IgM, IgG subclasses, and detectable pre-vaccination IgG antibodies against tetanus toxoid and Streptococcus pneumoniae. She was evaluated in our clinic in order to rule out common variable immunodeficiency. We observed good antibody response to tetanus toxoid, absence of circulating switched memory B cells, decreased response to pneumococcal polysaccharide antigens and a lack of response to Salmonella typhi vaccine. Most SIgAD patients presents with upper respiratory tract infections or mild diarrhea. Those with lower tract infections, pneumonia or untreatable diarrhea should follow B-cell subpopulations’ study and antibody response to vaccines. Absence of response to Salmonella typhi vaccine allowed us to expose the defective antibody production.

Background The antiphospholipid syndrome (APS) is defined by simultaneous presence of vascular clinical events and antiphospholipid antibodies (aPL). The aPL considered as diagnostics are lupus anticoagulant and antibodies anticardiolipin (aCL) and anti-s2 glycoprotein-I (aB2GP1). During recent years, IgA aB2GP1 antibodies have been associated with thrombotic events both in patients positive, and mainly negative for other aPL, however its value as a pro-thrombotic risk-factor in asymptomatic patients has not been well defined. Objective To test the role of IgA anti B2GP1 as a risk factor for the development of APS-events (thrombosis or pregnancy morbidity) in asymptomatic population with a 5-year follow-up. Methods 244 patients isolated positive for anti-beta2-glycoprotein I IgA (Group-1 study) and 221 negative patients (Group-2 control) were studied. All the patients were negative for IgG and IgM aCL. Results During the follow-up, 45 patients (9.7%) had APS-events, 38 positive for IgA-aB2GP1 and 7 negative (15.6% vs 3.2%, p