Objective
Despite long‐standing safe and effective use of immunoglobulin replacement therapy (IgRT) in primary immunodeficiency, clinical data on IgRT in patients with secondary immunodeficiency ...(SID) due to B‐cell lymphoproliferative diseases are limited. Here, we examine the correlation between approved IgRT indications, treatment recommendations, and clinical practice in SID.
Methods
An international online survey of 230 physicians responsible for the diagnosis of SID and the prescription of IgRT in patients with hematological malignancies was conducted.
Results
Serum immunoglobulin was measured in 83% of patients with multiple myeloma, 76% with chronic lymphocytic leukemia, and 69% with non‐Hodgkin lymphoma. Most physicians (85%) prescribed IgRT after ≥2 severe infections. In Italy, Germany, Spain, and the United States, immunoglobulin use was above average in patients with hypogammaglobulinemia, while in the UK considerably fewer patients received IgRT. The use of subcutaneous immunoglobulin was highest in France (34%) and lowest in Spain (19%). Immunologists measured specific antibody responses, performed test immunization, implemented IgRT, and used subcutaneous immunoglobulin more frequently than physicians overall.
Conclusions
The management of SID in hematological malignancies varied regionally. Clinical practice did not reflect treatment guidelines, highlighting the need for robust clinical studies on IgRT in this population and harmonization between countries and disciplines.
To analyze the implementation of the Principles of Care (PoC) in primary immunodeficiencies (PID) in Southeast Asia (SEA) countries - six years after its call of action.
Using the newly developed PID ...Life Index software, the index of implementation of principles of care in the management of PIDs patients involving the six participating SEA countries (Cambodia, Indonesia, Malaysia, Vietnam, Thailand, and Philippines) were extracted. For each of the six separate principles, the index from the six countries will be compared and presented based on the calculated index.
Comparative analysis of the six principles of care of PID in the SEA countries showed low diagnostic rate with minimal availability of diagnostic tests options. Generally, almost all SEA countries provide curative treatments, vaccines, and anti-infectious therapies although the reimbursement scheme varied in relieving patients' financial burden. We also highlighted the active involvement of patient organizations in SEA, with main areas of work focused on advocacy and increasing awareness among public and healthcare professionals.
It is applaudable that the SEA continent is gradually strengthening its work in management of PID, especially in Thailand and Vietnam. However, more emphasis must be placed among stakeholders in SEA countries towards successful implementation of the PoC for a holistic management of PID patients.
Recurrent respiratory tract infections (RRTIs) are the first leading cause of community‐ and nosocomial‐acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to ...develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat‐inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor‐interacting serine/threonine‐protein kinase‐2 (RIPK2)‐ and myeloid‐differentiation primary‐response gene‐88 (MyD88)‐mediated signalling pathways under the control of IL‐10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL‐10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections.
MV130, a polybacterial preparation to treat recurrent respiratory infections, promotes the generation of Th1, Th17 and IL‐10 immune responses against related and unrelated antigens via RIPK2 and MyD88‐mediated signalling pathways. These findings might well pave the way for alternative treatments in other clinical conditions with high risk of recurrent infections.
Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid ...tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1 , BCL10 , and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity.
There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of ...developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.
We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.
An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.
We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.
This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
Problem
Expansion of circulating NK cells has been related to pregnancy complications. This study aims at investigating several surface NK cell markers to identify a baseline inflammatory profile in ...women with recurrent pregnancy loss (iRPL) and recurrent implantation failure (iRIF).
Method of study
Expression of NKp30, TIGIT, NKp46, and DNAM‐1 on total peripheral blood NK subsets, regulatory (CD56brightCD16neg), and cytotoxic (CD56dimCD16pos/neg) NK cells was measured.
Results
Eighty‐three women were recruited and classified into two groups, 58 women with RPL and 25 with RIF. A control group of 31 fertile women was included. Expression of NKp30 on cytNK was significantly higher in RPL (p = .019) and RIF (p < .001) than HC. TIGIT on cytNK cells was also higher in both RPL (p < .001) and RIF (p < .01). An optimal cutoff of 70% for NKp30+ cytNK disclosed a sensitivity of 82%, a specificity of 55%, and 83% PPV for RPL diagnosis. A cutoff level of 83% for TIGIT+ cytNK was chosen to discriminate between healthy controls and RPL women, with PPV of 84%.
Conclusion
Our preliminary data on this RPL and RIF cohorts suggest a simple diagnostic tool by combining NKp30 and TIGIT on cytNK cells to better identify a subgroup of RPL and RIF patients with a baseline inflammatory profile. A more rigorous selection of these patients through phenotyping peripheral cytNK cells may better define patients that could benefit from an immunomodulatory treatment to prevent further pregnancy losses. The performance of these biomarkers requires further investigation and validation in independent cohorts.
Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological ...mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross‐sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1–67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C‐reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence‐based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.
Human blood monocytes are very potent to take up antigens. Like macrophages in tissue, they efficiently degrade exogenous protein and are less efficient than dendritic cells (DCs) at cross‐presenting ...antigens to CD8+ T cells. Although it is generally accepted that DCs take up tissue antigens and then migrate to lymph nodes to prime T cells, the mechanisms of presentation of antigens taken up by monocytes are poorly documented so far. In the present work, we show that monocytes loaded in vitro with MelanA long peptides retain the capacity to stimulate antigen‐specific CD8+ T cell clones after 5 days of differentiation into monocytes‐derived dendritic cells (MoDCs). Tagged‐long peptides can be visualized in electron‐dense endocytic compartments distinct from lysosomes, suggesting that antigens can be protected from degradation for extended periods of time. To address the pathophysiological relevance of these findings, we screened blood monocytes from 18 metastatic melanoma patients and found that CD14+ monocytes from two patients effectively activate a MelanA‐specific CD8 T cell clone after in vitro differentiation into MoDCs. This in vivo sampling of tumor antigen by circulating monocytes might alter the tumor‐specific immune response and should be taken into account for cancer immunotherapy.
What's new?
Dendritic cells are known to act as “antigen‐presenting cells” (APCs), which process tumor antigens and use them to prime and activate specific T cells. In this study, the authors found that monocytes can also take up tumor antigens, and can then differentiate into dendritic APCs, which can continue to stimulate tumor‐specific CD8+ T cells for a prolonged period of time. The authors conclude that this in vivo sampling of tumor antigen by circulating monocytes might alter the tumor‐specific immune response, and should be taken into account for cancer immunotherapy.
Abstract
Problem
Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) represent distinct clinical conditions with established definitions, both of which have been linked to an ...underlying pro‐inflammatory state. This study aimed to explore the levels of monocytic‐myeloid‐derived suppressor cells (M‐MDSCs) and regulatory T cells (T
Reg
) in a cohort of RPL and RIF women and their potential contribution to RPL and RIF.
Method of study
One hundred and eight non‐pregnant women were evaluated: 40 RPL, 41 RIF, and 27 fertile healthy controls (HC). A multiparametric flow cytometry approach was utilized to measure and quantify the frequency of M‐MDSCs and T
Reg
cells. Cytokine levels in plasma samples were evaluated through a multiplex assay. M‐MDSCs levels were significantly higher in RPL and RIF patients compared to HC.
Results
M‐MDSCs levels were significantly higher in RPL (9.4% 7–11.6) and RIF (8.1% 5.9–11.6) patients compared to HC (6% 4.2–7.6). An optimal cut‐off of 6.1% for M‐MDSCs disclosed a sensitivity of 75.6% and 89.7% and a specificity of 57.7% and 57.7% in RIF and RPL groups, respectively. A significant negative correlation was observed between M‐MDSCs and T
Reg
(
p
= .002,
r
= −.51).
Conclusions
Our preliminary data allowed us to build a predictive model that may aid as a potential diagnostic tool in the clinic. These findings could provide a better understanding of these pathologies and a better definition of patients that could benefit from personalized treatments to promote pregnancy. Additional exploration and confirmation in distinct study groups are needed to fully assess the diagnostic capabilities of this biomarker.
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