Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

IgD+IgM- B Cells in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent form of primary hypogammaglobulinemia in adults. In addition to recurrent infections and respiratory manifestations, CVID patients may present several non-infection complications such as autoimmune diseases. The mechanisms that lead to immune dysregulation in CVID are not completely understood. Given the role of IgD on naïve B cells in the maintenance of tolerance and secreted IgD in the respiratory mucosa, we evaluated the frequency of IgD+ naïve and IgD+ memory B cells in CVID patients. Here, no differences were observed in the percentages and proliferative responses of anergic IgD+IgM-CD27- B cells between CVID patients, with or without autoimmune disease, and the control group. Interestingly, in the compartment of memory B cells, the percentage of IgD+IgM- cells was higher only in CVID patients with allergic rhinitis/allergic asthma. Our results may indicate that anergic IgD+IgM-CD27- B cells may not be compromised in our CVID cohort. However, IgD+IgM- memory B cells may play a role in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients. Further studies are needed to better understand the participation of IgD+IgM- memory B cells in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients.

Improving the availability of antihypertensive drugs in the India Hypertension Control Initiative, India, 2019-2020.

BACKGROUND: Antihypertensive drug supply is sometimes inadequate in public sector health facilities in India. One of the core strategies of the India Hypertension Control Initiative (IHCI) is to improve the availability of antihypertensive drugs in primary and secondary care facilities. We quantified the availability of antihypertensive drugs in 2019-20 and described the practices in supply chain management in 22 districts across four states of India. METHODS: Twenty-two districts from 4 states (Punjab, Madhya Pradesh, Telangana, and Maharashtra) were studied. We described the practices and challenges in supply chain management. We collected data on drug procurement from 2018 to 2020 and drug availability from April 2019 to March 2020. Quantity procured, the proportion of facilities with stockout at the end of each quarter, and availability of drugs in patient days were tabulated. RESULTS: All states selected drug- and dose-specific protocols with Amlodipine as the initial drug and shifted to morbidity-based forecasting. The total number of antihypertensive tablets procured for the 22 districts increased from 16 million in 2017-2018 to 160 million in 2019-2020. The proportion of facilities with Amlodipine stock-out was below 5% during the study period. Amlodipine stock was available for at least 60 patient days from the third quarter of 2019 onward in all districts. CONCLUSIONS: This study demonstrates that including best practices can gradually strengthen the procurement and supply chain for antihypertensives in a low-resource setting. As the program was rapidly growing, there were still gaps in the procurement and distribution system which needed to be addressed to ensure the adequacy of drugs. We recommend that best practices, including choosing a single protocol, basing supply on projected patient load rather than an increment from historical levels, and using simple stock management tools, be replicated in other districts in India to increase and sustain coverage of hypertension treatment.

Leptin favors imbalance of antigen-specific CD4+ T-cells associated with severity of cat allergy.

Introduction: Obesity can complicate IgE-mediated allergic diseases. In the present study, we aimed to investigate the ability of obesity-related concentrations of leptin to modulate the in vitro effector and regulatory Fel d1-specific CD4+ T-cell subsets in patients allergic to cat, considered the third most common cause of respiratory allergy in humans. Methods: For this study, plasma and peripheral blood mononuclear cells (PBMC) from 30 cat-allergic patients with mild, moderate and severe respiratory symptoms were obtained. The PBMC cultures were stimulated with Fel d1 antigen (10 µg/mL) in the presence or absence of obesity-related leptin dose (50 ηg/mL). After 6 days, the levels of cytokines and IgE in the supernatants were evaluated by multiplex and ELISA, respectively. The frequency of different non-follicular (CXCR5-) and follicular (CXCR5+) Fel d1-specific CD4+ T cell subsets was determined by flow cytometry. The plasma levels of leptin and IgE anti-cat titers were evaluated by ELISA and ImmunoCAP, respectively. Results and conclusions: Fel d1 induced both IgE production and release of cytokines related to Th2, Th9 and Th17 cell phenotypes. Feld1 was more efficient in increasing the frequency of TFHIL-21- cells positive for IL-4, IL-5 and IL-13 than TFHIL-21+ cell subsets. Leptin favored the expansion Th2-like and Th9-like cells and TFHIL-21- cells positive for IL-4, IL-5 and IL-13, but reduced the proportion of conventional (Treg/Tr-1) and follicular (TFR) regulatory CD4+ T-cell subsets expressing or not CD39 marker. Finally, many of the imbalances between Fel d1-specific CD4+ T-cells were also correlated with plasma leptin and anti-Fel d1 IgE titers. In summary, hyperleptinemia should negatively impact on the severity of cat allergies by favoring the expansion of pathogenic Fel d1-specific CD4+ T-cell phenotypes and damaging the functional status of regulatory CD4+ T-cell subsets.

Stature estimation from the scapula measurements using 3D-volume rendering technique by regression equations in the Northern Indian population.

The present study assessed the correlation between the stature and scapular measurements from both sides in order to develop population-specific regression equations to estimate the stature from measurements of the scapula in a contemporary Northern Indian population individually for the left and right sides. A total of 597 cadavers underwent postmortem multidetector computed tomography and subsequent medicolegal autopsy in our department between August 2021 and August 2022. Two hundred samples (100 males and 100 females) were randomly collected based on inclusion and exclusion criteria. Six linear anthropometric measurements of the scapula from either side were measured using the 3D volume-rendered technique by an electronic cursor. Each anthropometric measurement showed a significant difference between males and females (p < 0.05). Regression analysis was applied to match the taken measurements against stature. The accuracy to predict stature ranged from 3.99 to 4.94 cm for males and from 4.49 to 5.27 cm for females, respectively. Left-sided measurements were better predictors of stature than the right side in both genders. The results of this study indicate that scapular measurements could be useful to estimate the stature of Northern Indian individuals, particularly in scenarios of disaster victim identification lacking long bones, which are considered to be better predictors to date.

Epidemio-toxicological profile of fatal poisoning cases autopsied at a tertiary care centre of North India.

Background: Poisoning is an important health hazard and one of the leading causes of morbidity and mortality worldwide including in India. The study was conducted to understand the magnitude, pattern, and gender differentials of all poisoning fatalities in relation to the manner of death autopsied at a tertiary care center. Methods: A retrospective study of all fatal poisoning cases autopsied at the department of Forensic Medicine & Toxicology of a tertiary care institute in Northern India for the period 1st January 1998 to 31st December 2017 was conducted, and a profile of the victims of fatal poisoning was prepared. Data were analyzed with descriptive and inferential statistics. Results: The study included a total of 1099 cases of fatal poisoning autopsied at the department of Forensic medicine & Toxicology. Suicidal poisoning was reported in 90.2% of cases and accidental poisoning was seen in 8.9% of cases. Males were predominantly affected (63.8%). The majority of the victims were in the 3rd decade (40.0%) of life. The age of the victims ranged from 2 to 82 years with a mean age of 38.4 years. Agrochemical compounds were implicated in 44.4% of the total fatalities. Conclusion: Males in the 2nd to 4th decades of life were more prone to self-poisoning with Agrochemical compounds in the region of North India. Accidental poisoning deaths were uncommon and poisoning was not a preferred method of homicide in this region. Our approach to the study reveals that quantitative chemical (toxicological) analysis is required to further strengthen and improve the databases of the epidemiology of poisoning in this region.

Subcutaneous Immunoglobulin 16.5% (Cutaquig®) in Primary Immunodeficiency Disease: Safety, Tolerability, Efficacy, and Patient Experience with Enhanced Infusion Regimens.

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

Infections in DNA Repair Defects.

DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.

Dendritic cells in inborn errors of immunity.

Dendritic cells (DCs) are crucial cells for initiating and maintaining immune response. They play critical role in homeostasis, inflammation, and autoimmunity. A number of molecules regulate their functions including synapse formation, migration, immunity, and induction of tolerance. A number of IEI are characterized by mutations in genes encoding several of these molecules resulting in immunodeficiency, inflammation, and autoimmunity in IEI. Currently, there are 465 Inborn errors of immunity (IEI) that have been grouped in 10 different categories. However, comprehensive studies of DCs have been reported in only few IEI. Here we have reviewed biology of DCs in IEI classified according to recently published IUIS classification. We have reviewed DCs in selected IEI in each group category and discussed in depth changes in DCs where significant data are available regarding role of DCs in clinical and immunological manifestations. These include severe immunodeficiency diseases, antibody deficiencies, combined immunodeficiency with associated and syndromic features, especially disorders of synapse formation, and disorders of immune regulation.

A new "Stethoscope" autopsy incision in comparison to various conventional incisions along with suturing techniques and body packing methods for post autopsy reconstruction.

Post autopsy reconstruction (PAR) plays a vital role in the external appearance of dead bodies while handing over to grieving family members. Autopsy surgeons should not only be restricted to autopsy findings/techniques but should also give importance to PAR. Autopsy incision includes various conventional incisions like I, Y, and Modified Y-shaped. The most commonly used incision is I -shaped in most of the autopsy because it is easy for quick suturing but it produces a poor cosmetic appearance because suturing produces visible suture over the front of the neck and chest of a corpse and improper suturing in the skin flaps leads to gapping causes leakage of body fluids at the suture site. More often that leads to avoidable, unnecessary emotional distress for grieving family members. That creates a negative image of forensic practice in society and sometimes with administrative complaints. The authors conducted an observation based study on the medicolegal autopsy that included ten cases that involved "Stethoscope" and various conventional incisions and explored suturing techniques and body packing methods. The study observed that the proposed "Stethoscope" incision was feasible, less time-consuming for suturing, had an excellent cosmetic effect, and was cost-effective. The suturing technique revealed that invisible sutures leads to good cosmetic outcomes but is more time-consuming and costly. The body packing method showed the excellent result of no leakage of body fluid from the suture site. The authors proposed a "Stethoscope" method of incision that can be practiced and adopted for a better cosmetic appearance and humanitarian aspect for grieving relatives. The body packing method renders the body non-hazardous to the public and attendants while handling and transporting. The authors highlight the importance and sensitization of autopsy surgeon/mortuary staff to restructure the corpse with the best cosmetic appearance for the Dignified Management of the Dead and Humanitarian Forensics.

The India Hypertension Control Initiative-early outcomes in 26 districts across five states of India, 2018-2020.

Hypertension is the leading single preventable risk factor for cardiovascular disease. The India Hypertension Control Initiative (IHCI) project was designed to improve hypertension control in public sector clinics. The project was launched in 2018-2019 in 26 districts across five states: Punjab (5), Madhya Pradesh (3), Kerala (4), Maharashtra (4), and Telangana (10), with five core strategies: standard treatment protocol, reliable supply of free antihypertensive drugs, team-based care, patient-centered care, and an information system to track individual patient treatment and blood pressure control. All states implemented simple treatment protocols with three drugs: a long-acting dihydropyridine calcium channel blocker (amlodipine), angiotensin receptor blocker (telmisartan), and thiazide or a thiazide-like diuretic (hydrochlorothiazide or chlorthalidone). Medication supplies were adequate to support at least one month of treatment. Overall, 570,365 hypertensives were enrolled in 2018-2019; 11% did not have follow-up visits in the most recent 12 months. Clinic-level blood pressure control averaged 43% (range 22-79%) by Jan-March, 2020. The proportion of the estimated people with hypertension who had it controlled and documented in public clinics increased three-fold, albeit from very low levels (1.4-5.0%). The IHCI demonstrated the feasibility of implementing protocol-based hypertension treatment and control supported by a reliable drug supply and accurate information systems at scale in Indian primary health care facilities. Lessons from the IHCI's initial phase will inform plans to improve screening in health care facilities, increase retention in care, and ensure a sustained supply of drugs as part of a nationwide hypertension control program.

Subcutaneous immunoglobulin 16.5% for the treatment of pediatric patients with primary antibody immunodeficiency.

INTRODUCTION: Human immunoglobulin (IG) administered intravenously (IVIG) or subcutaneously (SCIG) is used to prevent infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. AREAS COVERED: This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. EXPERT OPINION: Individualized treatment for PIDD in children is necessary given the different factors that affect administration of SCIG. Variables such as the dose, dosing interval, administration sites, and ancillary equipment can be adjusted to impact the long-term satisfaction with SCIG administration in pediatric patients. The successful work that has been conducted by both professional and patient organizations to increase awareness of PIDD, especially in pediatric patients, is substantial and ongoing. The importance of early diagnosis and treatment in the pediatric patient population cannot be overstated. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.

Human immunoglobulin (IG) is extracted from the plasma of donors as a sterile, purified blood product that is administered intravenously (via a vein [IVIG]) or subcutaneously (under the skin [SCIG]) and is used for a variety of disorders, including the prevention of infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. The importance of early identification of PIDD, especially in pediatric patients, cannot be overstated to ensure prompt treatment. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.

The Impact of Long-Term Orientation Traits on Pandemic Fatigue Behavior: Evidence from the Columbian Exchange.

Leveraging exogenous variation in time preferences, we measure the causal effects of culturally embodied long-term orientation traits on voluntary social distancing behavior, COVID-19 cases, hospitalizations, and mortality outcomes in 2020 in the United States. We establish that long-term orientation traits with bio-geographical origins causally reduce measures of COVID-19 cases, deaths and hospitalization, inpatient bed utilization, and age-specific excess deaths. Mobility indicators measuring voluntary decisions to socially distance, comprising measures of visitors/visits to recreational locations, and mobility proxy measuring duration of hours away from home show that a lower prevalence of long-term orientation traits explains persistent resistance to social distancing. Supplementary Information: The online version contains supplementary material available at 10.1007/s10887-022-09218-0.

Long-term efficacy, safety, and tolerability of a subcutaneous immunoglobulin 16.5% (cutaquig®) in the treatment of patients with primary immunodeficiencies.

A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up.

Post-mortem CT: A Useful Tool to Confirm a Case of Suspected Sudden Cardiac Death.

Sudden cardiac death (SCD) is defined as the unexpected death of an individual, not due to any extracardiac cause, occurring within one hour of symptom onset or within 24 hours of last being seen in good health if the death is unwitnessed. Forensic pathologists routinely encounter several SCD cases in their practice. The presentation of such cases can be of two types; firstly, with typical signs and symptoms suggestive of cardiac pathology, and secondly, devoid of any presentation history. This history helps forensic pathologists look for relevant findings during the autopsy examination. The authors intend to explore the feasibility of using advanced radiological techniques like post-mortem CT (PMCT) in determining the cause of death through a minimally invasive approach. In the present case, a 65-year-old male was found unresponsive at his residence on the morning of his death. He had a history of dull chest pain for the past two days, which had resolved after he self-prescribed a few medications. The presenting complaint of chest pain had started the intervening night prior to his death. The deceased was a known case of hypertension and was not compliant with treatment, as stated by the relatives. He was declared as brought dead by the treating emergency medicine physician at the Fortis Flt. Lt. Rajan Dhall Hospital and the body was sent by the authorities to the mortuary of the Department of Forensic Medicine, AIIMS, New Delhi for autopsy examination since an autopsy should be conducted by a government hospital or institute by law. PMCT depicted an alternate hyperdense and hypodense region circumferentially surrounding the heart, indicating hemopericardium. It was followed by a traditional autopsy and histopathology examination, which confirmed the presence of hemopericardium and left ventricular rupture associated with acute coronary insufficiency. Such cases with an indicative history, circumstantial evidence, and PMCT findings can be considered for minimal invasive autopsy. If the external findings indicate the application of physical force, then an explorative dissection could be done. Therefore, we conclude that PMCT can be used as a reliable tool for determining the cause of death in SCDs on a case-to-case basis.

Suicide numbers during the first 9-15 months of the COVID-19 pandemic compared with pre-existing trends: An interrupted time series analysis in 33 countries.

Background: Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally. Methods: We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation. Findings: We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries' COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries' income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well. Interpretation: Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue. Funding: None.

Leptin favors Th17/Treg cell subsets imbalance associated with allergic asthma severity.

Background: Obesity has often been associated with severe allergic asthma (AA). Here, we analyzed the frequency of different circulating CD4+T-cell subsets from lean, overweight and obese AA patients. Methods: Mononuclear cells from peripheral blood were obtained from 60 AA patients and the frequency of different CD4+T-cell subsets and type 1 regulatory B cells (Br1) was determined by cytometry. The effect of obese-related leptin dose on cytokine production and Treg cell function in AA-derived CD4+ T cell cultures was evaluated by ELISA and 3H thymidine uptake, respectively. Leptin levels were quantified in the plasma by ELISA. According to the BMI, patients were stratified as lean, overweight and obese. Results: AA severity, mainly among obese patients, was associated with an expansion of hybrid Th2/Th17 and Th17-like cells rather than classic Th2-like cells. On the other hand, the frequencies of Th1-like, Br1 cells and regulatory CD4+ T-cell subsets were lower in patients with severe AA. While percentages of the hybrid Th2/Th17 phenotype and Th17-like cells positively correlated with leptin levels, the frequencies of regulatory CD4+ T-cell subsets and Br1 cells negatively correlated with this adipokine. Interestingly, the obesity-related leptin dose not only elevated Th2 and Th17 cytokine levels, but also directly reduced the Treg function in CD4+ T cell cultures from lean AA patients. Conclusion: In summary, our results indicated that obesity might increase AA severity by favoring the expansion of Th17-like and Th2/Th17 cells and decreasing regulatory CD4+T cell subsets, being adverse effects probably mediated by leptin overproduction.

Members of the Regulatory Lymphocyte Club in Common Variable Immunodeficiency.

The role of CD4 T regulatory cells is well established in peripheral tolerance and the pathogenesis of the murine model and human autoimmune diseases. CD4 T regulatory cells (CD4 Tregs) have been investigated in common variable immunodeficiency (CVID). Recently, additional members have been added to the club of regulatory lymphocytes. These include CD8 T regulatory (CD8 Tregs), B regulatory (Bregs), and T follicular helper regulatory (TFR) cells. There are accumulating data to suggest their roles in both human and experimental models of autoimmune disease. Their phenotypic characterization and mechanisms of immunoregulation are evolving. Patients with CVID may present or are associated with an increased frequency of autoimmunity and autoimmune diseases. In this review, we have primarily focused on the characteristics of CD4 Tregs and new players of the regulatory club and their changes in patients with CVID in relation to autoimmunity and emphasized the complexity of interplay among various regulatory lymphocytes. We suggest future careful investigations of phenotypic and functional regulatory lymphocytes in a large cohort of phenotypic and genotypically defined CVID patients to define their role in the pathogenesis of CVID and autoimmunity associated with CVID.

SARS-CoV-2-Specific and Functional Cytotoxic CD8 Cells in Primary Antibody Deficiency: Natural Infection and Response to Vaccine.

PURPOSE: CD8 cytotoxic T cells (CTLs) play a critical role in the clearance of virally infected cells. SARS-CoV-2-specific CD8 T cells and functional CTLs in natural infections and following COVID-19 vaccine in primary antibody deficiency (PAD) have not been reported. In this study, we evaluated T cell response following COVID-19 or COVID-19 mRNA vaccination in patients with PADs by assessing SARS-CoV-2 tetramer-positive CD8 T cells and functional CTLs. METHODS: SARS-CoV-2-specific CD8 and functional CTLs were examined in a patient with X-linked agammaglobulinemia (XLA) and a patient with common variable immunodeficiency (CVID) following COVID-19 infection, and in 5 patients with CVID and 5 healthy controls 1 month following 2nd dose of COVID-19 mRNA vaccine (Pfizer-BioNTech). Cells were stained with SARS-CoV-2 spike protein-specific tetramers, and for functional CTLs (CD8+ CD107a+ granzyme B+ perforin+), with monoclonal antibodies and isotype controls and analyzed by flow cytometry. RESULTS: SARS-CoV-2-specific tetramer + CD8 T cells and functional CTLs in the patient with XLA following COVID-19 infection were higher, as compared to healthy control subject following COVID-19 infection. On the other hand, SARS-CoV2-tetramer + CD8 T cells and functional CTLs were lower in CVID patient following COVID19 infection as compared to healthy control following COVID-19 infection. SARS-CoV2-tetramer + CD8 T cells and functional CTLs were significantly lower in SARS-CoV2-naive CVID patients (n = 10) following vaccination when compared to SARS-CoV-2-naive healthy vaccinated controls (n = 10). CONCLUSIONS: CVID is associated with reduced SARS-CoV-2-specific CD8 T cells and functional CTLs in both natural SARS-CoV-2 infection and in response to SARS-CoV-2 mRNA vaccine, whereas natural infection in XLA is associated with a robust SARS-CoV-2-specific CD8 and functional CTL responses.