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Primary splenic diffuse large B-cell lymphoma (PS-DLBCL) is a relatively rare malignancy, and there are no optimal approaches for diagnosis and management. There are less invasive splenic biopsies that effectively obviate diagnostic and elective splenectomies. We report a man in his 50s with 2-day history of pain in the abdomen and who was found to have a splenic mass on PET-CT. A CT-guided core needle splenic biopsy confirmed the diagnosis of PS-DLBCL. He was managed with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alone, without splenectomy. The patient attained complete remission, and he is disease free at 6 years of follow-up.

Objectives: Identification of the high risk alleles, genotypes and haplotypes of the human leukocyte antigens (HLA) in different populations is beneficial for understanding their roles in type 1 diabetes (T1D) pathogenesis and intervention practices. This study aimed to identify T1D-associated HLA gene alleles in the Omani population. Methods: The present case-control study included 73 diabetic seropositive children (mean age 9.08 ± 3.27 years) attending the paediatric clinic at Sultan Qaboos University Hospital in Muscat, Oman, and 110 healthy controls. HLA–A, -B, -C, -DRB1 and -DQB1 genes were genotyped using a sequence-specific primer polymerase chain reaction (SSP-PCR). Results: Two HLA class I alleles (B*08, B*58) and three class II alleles (DQB1*02, DRB1*03 and DRB1*04) were associated with T1D susceptibility, while one class I (B*51) and three class II (DQB1*05, DQB1*06 and DRB1*16) alleles were associated with T1D protection. HLA-DRB1*03 and DQB1*02 alleles showed the strongest risk association among all alleles. Six DRB1 residues (E9, S11, S13, Y30, V70 and K71) were significantly associated with T1D susceptibility. Heterozygous genotypes, HLA-DRB1*03/*04 and DQB1*02/*03 were significantly associated with T1D susceptibility (P

ObjectivesRecent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations.MethodsRecommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement.ResultsIn general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles–mumps–rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients.ConclusionsThese recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.

Abstract: Although metabolic tumor volume (MTV) assessed with pretreatment 18F-FDG PET/CT has shown significant prognostic value across many lymphoma types, it is still not used in clinical practice due to technical concerns and the lack of standardisation. Numerous studies on the prognostic value of MTV in lymphomas have been published in recent years, but there is still no full agreement on the best methodology for MTV calculation. In this paper, we reviewed the methodological aspects of MTV assessment and reported recent works about its impact on outcome in lymphomas, with a focus on Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL).

Teucrium polium has been used in traditional medicine around the world for centuries in treatment of various conditions and diseases. Many studies have confirmed pharmacological effects of its extracts, although the immunomodulatory effect has not been investigated. Therefore, the aim of our study was to examine the immunomodulatory effect of methanolic extract of T. polium (TPE) on peripheral blood mononuclear cells (PBMCs) derived from healthy donors and patients with hepatitis C virus HCV infection. We analyzed the effect of the extract on PBMCs viability using the MTT test. The cell death type was determined using Annexin V-FITC/7-AAD staining. Immunophenotyping using anti-CD8 FITC, anti-CD4 PE, anti-CD3 ECD, anti-CD20 PC5, anti-CD14 FITC and anti-CD25 PC7 was performed by flow cytometry. Results of the MTT test indicate that TPE stimulates proliferation of healthy PBMCs, while the HCV PBMCs viability was slightly reduced. The percentage of apoptotic HCV PBMCs was higher after TPE treatment compared to the control. The proportion of CD25-expressing cells was higher among the untreated HCV PBMCs than in the untreated healthy PBMCs. TPE treatment significantly and gradually increased CD25 expression in healthy PBMCs, whereas CD25 expression on HCV PBMCs increased only at the highest TPE concentration. The upregulation of double-positive CD3+CD25+, CD20+CD25+ and CD14+CD25+ cells was significant in TPE treated healthy PBMCs, while only the highest concentration was effective on HCV PBMCs. In summary, TPE exerts a strong immunomodulatory effect on healthy PBMCs and, only at the highest concentration, on HCV PBMNCs.

Chronic inducible urticaria (CIndU) is a subset of chronic urticaria that has an identifiable trigger. We present a case of postural urticaria induced by change in position in a 14-year-old girl. The patient’s CIndU was not adequately managed with both antihistamine and omalizumab treatment, indicating a recalcitrant form of CIndU.

COVID-19 is the disease caused by SARS-CoV-2 which has led to 2,643,000 deaths worldwide, a number which is rapidly increasing. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify drugs that can target the overactive immune response are ongoing. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19. However, there is limited data as to the course of COVID-19 in people living with HIV, with some studies showing a decreased mortality for those taking certain ARV regimens. We hypothesized that ARVs other than lopinavir and ritonavir might be responsible for some protection against the progression of COVID-19. Here, we used chemoinformatic analyses to predict which ARVs would bind and potentially inhibit the SARS-CoV-2 main protease (Mpro) or RNA-dependent-RNA-polymerase (RdRp) enzymes in silico. The drugs predicted to bind the SARS-CoV-2 Mpro included the protease inhibitors atazanavir and indinavir. The ARVs predicted to bind the catalytic site of the RdRp included Nucleoside Reverse Transcriptase Inhibitors, abacavir, emtricitabine, zidovudine, and tenofovir. Existing or new combinations of antiretroviral drugs could potentially prevent or ameliorate the course of COVID-19 if shown to inhibit SARS-CoV-2 in vitro and in clinical trials. Further studies are needed to establish the activity of ARVs for treatment or prevention of SARS-CoV-2 infection . Communicated by Ramaswamy H. Sarma

This study aims to identify associations between nocturnal asthma awakenings and functional health outcomes in a cohort of teenagers with asthma.We analyzed baseline data from teenagers enrolled in SB-ACT, an NIH-funded RCT. During an at-home baseline survey, teenagers with asthma answered questions about demographics, recent asthma symptoms, and functional health outcomes. We conducted regression analyses to explore the relationship between persistent nocturnal asthma symptoms (≥2 nights of nocturnal asthma awakenings in the past 14 days) and functional health measures.Of the 430 teens enrolled (Participation rate = 79%, Mean Age = 13.4), 30% reported persistent nocturnal asthma symptoms. Compared to teens with intermittent nocturnal asthma symptoms, teens with persistent nocturnal asthma symptoms were more likely to report physical limitation during strenuous activities (OR = 1.9, 1.3-3.0), moderate activities (OR = 1.9, 1.2-3.1), and school gym (OR = 2.4, 1.5-3.8). They were also more likely to report depressive symptoms (OR = 2.3, 1.5-3.6), more asthma-related school absenteeism in the past 14 days (0.81 vs 0.12, plt; 0.01) and poorer quality of life (4.6 vs 5.9, plt; 0.01). These findings remained significant when controlling for daytime asthma symptoms, weight status, race, ethnicity, gender, age, and smoke exposure.In this cross-sectional study, persistent nighttime asthma symptoms were associated with poor functional health outcomes among teens, independent of day-time symptoms. Identifying nighttime symptoms and improving asthma control at night may positively impact daily functioning for these teens.

Patients with immune-mediated inflammatory diseases (IMIDs) receiving B cell-depleting therapy (BCDT) are among the most vulnerable to severe COVID-19, as well as the most likely to suboptimally respond to SARS-CoV-2 vaccines. However, little is known about the frequency or severity of breakthrough infection in this population. We retrospectively analyzed a large group of vaccinated IMID patients undergoing BCDT in order to identify breakthrough COVID-19 infections and assess their outcomes.In this retrospective cohort study, the pharmacy records and COVID-19 registry at the Cleveland Clinic were searched using specific International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes to identify IMIDs patients who 1) received treatment with BCDT, 2) were vaccinated against SARS-CoV-2, and 3) experienced breakthrough infections. Each electronic medical record was reviewed to extract clinical data and outcomes. Univariate and multivariable logistic/proportional odds regression models were used to examine the risk factors for severe outcomes.Of 1,696 IMID patients receiving BCDT, 74 developed breakthrough COVID-19 prior to December 16, 2021. Outcomes were severe, with 29 patients hospitalized (39.2%), 11 patients requiring critical care (14.9%), and 6 deaths (8.1%). Outpatient anti-SARS-CoV-2 monoclonal antibodies were used to treat 21 patients, with 1 hospitalization and no deaths. A comparator analysis examining 1,437 unvaccinated IMID patients receiving BCDT over the same time period identified 57 COVID-19 cases (4.0%), with 28 requiring hospitalization (49.1%), including 7 deaths (12.3%).IMID patients receiving BCDT regardless of vaccine status appear to be vulnerable to infection with SARS-CoV-2, and use of BCDT is frequently associated with severe outcomes. Outpatient use of anti-SARS-CoV-2 monoclonal antibody therapy appears to be associated with enhanced clinical outcomes.

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells, whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in 2 xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21–expanded NK cells. Collectively, these data support development of mbIL-21–expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK− anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) after frontline treatment with A+CHP or cyclophosphamide, doxorubicin, vincristine, and prednisone. Median PFS follow-up was 47.57 months. The PFS hazard ratio was 0.36, equating to a 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached, vs 55.66 months in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK− ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30+PTCL who achieve CR following treatment with A+CHP.

IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, whether CD5 directly regulates IL-15–induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15–induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15–induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15–induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.

Contact allergy can manifest in a variety of ways clinically. Systemic contact allergy may occasionally present with pain in muscles and joints. Fibromyalgia is a chronic rheumatic disease characterized by pain and with virtually unknown aetiology.The aim of this study was to investigate the contact allergy rates to the sensitizers in a baseline series and compare with corresponding rates in dermatitis patients and the general population.Patch testing with the Swedish baseline series was performed in 120 individuals with fibromyalgia. Fisher's exact test was used for pair-wise comparisons of contact allergy rates between the fibromyalgia group and two control groups, dermatitis patients and individuals in the general population.Contact allergy was significantly more common in the fibromyalgia group compared to the general population concerning nickel and the fragrance markers Myroxolon pereirae and fragrance mix I. There were fewer allergic reactions to preservatives in the fibromyalgia group compared with the dermatitis group.Myroxolon pereirae and fragrance mix I represent besides fragrance allergy also allergy to flavouring substances which indicate that oral exposure to flavouring substances and hygiene products might be important for sensitization and possibly elicitation of systemic contact allergy symptoms in fibromyalgia individuals.

Previous work identified three subgroups of children with ASD based upon co-occurring conditions (COCs) diagnosed during the first 5 years of life. This work examines prenatal risk factors, given by maternal medical claims, for each of the three subgroups: children with a High-Prevalence of COCs, children with mainly developmental delay and seizures (DD/Seizure COCs), and children with a Low-Prevalence of COCs. While some risk factors are shared by all three subgroups, the majority of the factors identified for each subgroup were unique; infections, anti-inflammatory and other complex medications were associated with the High-Prevalence COCs group; immune deregulatory conditions such as asthma and joint disorders were associated with the DD/Seizure COCs group; and overall pregnancy complications were associated with the Low-Prevalence COCs group. Thus, we have found that the previously identified subgroups of children with ASD have distinct associated prenatal risk factors. As such, this work supports subgrouping children with ASD based upon COCs, which may provide a framework for elucidating some of the heterogeneity associated with ASD.

Biomarkers that predict the risk of immune-mediated adverse events (irAEs) among patients with non-small cell lung cancer (NSCLC) may reduce morbidity and mortality associated with these treatments.We carried out high resolution human leucocyte antigen (HLA)-I typing on 179 patients with NSCLC treated with anti-program death (PD)-1/program death ligand (PDL)-1. Toxicity data were collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We used 14.8-week for landmark analysis to address lead-time bias to investigate the correlation between HLA-I/II zygosity, supertypes and alleles with irAE. Furthermore, we assessed the association for irAE with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS).Homozygosity at one or more HLA-I loci, but not HLA-II, was associated with a reduced risk of irAE (relative risk (RR) = 0.61, 95% CI 0.33-0.95, P = 0.035) especially pneumonitis or any grade 3 toxicity. Patients with HLA-A03 supertype had a higher risk of developing irAE (RR = 1.42, 95% CI 1.02-2.01, P = 0.039). The occurrence of any irAE was significantly associated with improved CBR (RR = 1.48, P lt; 0.0001), PFS (HR = 0.45, P = 0.0003) and OS (HR = 0.34, P lt; 0.0001).Homozygosity at one or more HLA-I loci may serve as biomarker to predict patients who are unlikely to experience severe irAEs among patients with NSCLC and treated with anti-PD1/PDL1, but less likely to derive clinical benefit. Patients with HLA-I homozygous might benefit from additional therapy.

Non-Hodgkin lymphomas (NHL) represent the most common hematologic malignancies. Patient-derived xenografts (PDXs) are used for various aspects of translational research including preclinical in vivo validation of experimental treatment approaches. While it was repeatedly demonstrated that PDXs keep majority of somatic mutations with the primary lymphoma samples, from which they were derived, the composition of PDX tumor microenvironment (TME) has not been extensively studied. We carried out a comparative genetic and histopathological study of 15 PDX models derived from patients with various types of NHL including diffuse large B-cell lymphoma (DLBCL; n = 7), Burkitt lymphoma (BL; n = 1), mantle cell lymphoma (MCL; n = 2), and peripheral T-cell lymphomas (PTCL; n = 5). Whole exome sequencing (WES) of the PDXs and primary lymphoma cells was implemented in 13 out of 15 cases with available DNA samples. Standard immunohistochemistry (IHC) was used to analyze the composition of PDX TME. WES data confirmed that PDXs maintained the genetic heterogeneity with the original primary lymphoma cells. In contrast, IHC analysis revealed the following recurrently observed alterations in the composition of PDX tumors: more blastoid lymphoma cell morphology, increased proliferation rate, lack of non-malignant cellular components including T cells and (human or murine) macrophages, and significantly lower intratumoral microvessel density and microvessel area composed of murine vessels. In addition, PDX tumors derived from T-NHL displayed additional differences compared to the primary lymphoma samples including markedly lower desmoplasia (i.e., the extent of both reticular and collagen fibrosis), loss of expression of cytotoxic granules (i.e., perforin, TIA, granzyme B), or loss of expression of T-cell specific antigens (i.e., CD3, CD4, CD8). Our data suggest that despite keeping the same genetic profiles, PDX models of aggressive NHL do not recapitulate the microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH). Methods Data for patients with AIH and SARS-CoV-2 infection were combined from three international reporting registries and outcomes were compared to those with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD). Results Between 25th March and 24th October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) of AIH patients were taking one or more immunosuppressive drug. There were no differences in rates of major outcomes between AIH and non-AIH CLD including hospitalization (76% vs 85%; p= 0.06), ICU admission (29% vs. 23%; p=0.240), and death (23% vs. 20%; p=0.643). Factors associated with death within the AIH cohort included age (OR 2.16/10 years; 1.07–3.81), Child-Turcotte-Pugh (CTP) class B (OR 42.48; 4.40–409.53), and CTP-C cirrhosis (OR 69.30; 2.83–1694.50), but not use of immunosuppression. Propensity score matched (PSM) analysis comparing AIH with non-AIH CLD demonstrated no increased risk adverse outcomes including death (+3.2%; -9.2%–15.7%). PSM analysis of AIH versus non-CLD patients (n=769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6–31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%–15.6%). Conclusion AIH patients were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease., Graphical abstract, Highlights • This is the largest cohort of patients with autoimmune hepatitis and laboratory proven SARS-COV-2 infection reported to date. • There were no differences in rates of major adverse COVID-19 outcomes including hospitalization, intensive care unit (ICU) admission, and death between AIH patients and those with other aetiologies of liver disease. • When compared to patients without liver disease in propensity score matched analysis, patients with AIH had higher rates of hospitalization but no increased risk of ICU admission or death despite potential reporting of AIH cases with more severe baseline liver disease. • Independent risk factors for death in AIH patients were age and baseline liver disease severity, but not the use of immunosuppression., Lay summary: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from three large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.

Follicular lymphoma (FL) is one of the most common types ofNon-Hodgkin Lymphoma (NHL) which originates from B-cells.1Generally it has an indolent clinical course, althoughhistological transformation to aggressive lymphoma mayoccur in 25-35 % of cases, and therafter the prognosis hasbeen reported to be poor. Transformation to histiocytic sar-coma may also be seen but very rarely 2-s2.0-85116800278

The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low-density lipoprotein, defective clearance of dead cells, and inflammation, with a pro-inflammatory T-cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non-mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro-inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti-PC) and other small lipid-related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti-PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.

Rituximab (RTX), a chimeric monoclonal antibody targeting CD20-positive cells, is a valuable treatment option for malignant and benign immune-related disorders. The rationale of targeting the CD20 antigen relies on depletion of both healthy and autoreactive/malignant CD20-espressing cells, but normal B-cell reconstitution is expected within months after treatment. Nevertheless, a number of recent studies have documented prolonged B-cell deficiency associated with new-onset hypogammaglobulinemia in patients receiving RTX. Awareness of post-RTX hypogammaglobulinemia has become wider among clinicians, with a growing number of reports about the increased incidence, especially in children. Although these patients were previously regarded as affected by secondary/iatrogenic immunodeficiency, atypical clinical and immunological manifestations (e.g., severe or opportunistic infections; prolonged B-cell aplasia) raise concerns of delayed manifestations of genetic immunological disorders that have been unveiled by B-cell perturbation. As more patients with undiagnosed primary immune deficiency receiving RTX have been identified, it remains the challenge in discerning those that might display a higher risk of persistent RTX-associated hypogammaglobulinemia and need a tailored immunology follow-up. In this review, we summarize the principal evidence regarding post-RTX hypogammaglobulinemia and provide a guideline for identifying patients at higher risk of RTX-associated hypogammaglobulinemia that could harbor an inborn error of immunity.

Background: We examined the impact of race/ethnicity and age on survival in a publicly insured cohort of children and adolescent/young adults (AYA; 15–39 years) with Hodgkin lymphoma, adjusting for...

We report a case of multiple high-grade and rare immune-related adverse events (irAEs) in a patient with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A middle-aged MSI-H mCRC patient with metastases to the lungs and lymph nodes received several lines of chemotherapy and immunotherapy and developed five different high-grade irAEs during immunotherapy, including lymphadenitis, pneumonitis, hypophysitis, thyroiditis and transverse myelitis. Genomic profiling revealed high tumor mutational burden of 43 Muts/Mb. Cytokine profiling showed a threefold increase in MMP-9 shortly prior to the onset of lymphadenitis and a fourfold increase of Ang-1 1 week after the resolution of lymphadenitis. Further studies are warranted to investigate the association of MSI-H mCRC with irAEs and the role of cytokines in predicting irAEs.Immune-related adverse events (irAEs) are a potential side effect of taking immunotherapy treatment for cancer. We report a case of a patient with a highly mutated form of metastatic colon cancer who developed five unique and severe irAEs while receiving immunotherapy. The patient developed inflammation of the lymph nodes, lungs, pituitary gland, thyroid and spinal cord. Genetic testing showed that the tumor was highly mutated (43 Muts/Mb). Analysis of cell signaling proteins called cytokines revealed that MMP-9 sharply increased before the onset of lymphadenitis and Ang-1 sharply increased after its resolution. Further research is needed to understand the relationship between highly mutated colon cancer and irAEs as well as the role of cytokines in predicting the onset and resolution of irAEs.

As the coronavirus disease (COVID-19) pandemic led to a global health crisis, there were limited treatment options and no prophylactic therapies for those exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma is quick to implement, potentially provides benefits, and has a good safety profile. The therapeutic potential of COVID-19 convalescent plasma (CCP) is likely mediated by antibodies through direct viral neutralization and Fc-dependent functions such as a phagocytosis, complement activation, and antibody-dependent cellular cytotoxicity. In the United States, CCP became one of the most common treatments with more than a half million units transfused despite limited efficacy data. More than a dozen randomized trials now demonstrate that CCP does not provide benefit for those hospitalized with moderate to severe disease. However, similar to other passive antibody therapies, CCP is beneficial for early disease when provided to elderly outpatients within 72 hours after symptom onset. Only high-titer CCP should be transfused. CCP should also be considered for immunosuppressed patients with COVID-19. CCP collected in proximity, by time and location, to the patient may be more beneficial because of SARS-CoV-2 variants. Additional randomized trial data are still accruing and should be incorporated with other trial data to optimize CCP indications.

Epidemiologic studies are starting to report associations between antibiotic use in early life and neurodevelopmental disorders. Through mechanisms within the gut microbiota-brain axis, indeed, it is plausible that infant antibiotic treatment plays a role in the development of atopic disease and neurodevelopmental disorders.This narrative review summarizes and interprets published evidence on infant antibiotic use in future outcomes of atopic disease, and neurodevelopmental delay and disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). To this end, we critically assess study bias from two main confounding factors, maternal/infant infection and infant feeding status. We also discuss common mechanisms that link atopy and neurodevelopment, and propose hypotheses related to immune activation and the gut microbiome.Atopic disease and neurodevelopmental disorders share many risk factors and biological pathways. Infant antibiotic use has been linked to both disorders and is likely a marker for prenatal or infant infection. The mediating role of breastfeeding can also not be discounted. The exploration of causal pathways along the gut-brain axis leading toward neurodevelopmental impairment is evolving and of future interest.

Systemic lupus erythematosus (SLE) patients have more pregnancy complications than healthy patients. Data regarding pregnancy outcomes in women with undifferentiated connective tissue disease (UCTD) are more limited, and existing studies are concentrated in Italy and predominantly in patients with a new diagnosis. Our objective was to compare pregnancy outcomes for UCTD and SLE patients with established disease.Between 2008 and 2017, patients with UCTD and SLE at an academic medical center were recruited to a prospective pregnancy registry. UCTD was defined as a positive autoantibody plus connective tissue disease symptoms not meeting criteria for another rheumatic diagnosis. SLE was defined by American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria or by physician diagnosis. Data were collected throughout pregnancy and postpartum. Comparator groups included UCTD, low-activity SLE, and high-activity SLE.A total of 150 SLE and 51 UCTD pregnancies were analyzed. Disease activity was low in most patients, although more patients with SLE had severe activity during pregnancy (12% versus 2%; P = 0.05). The frequencies of prematurity and preeclampsia were significantly lower in UCTD than in high-activity SLE patients (preterm 17% versus 45% [P = 0.004] and preeclampsia 6% versus 34% [P = 0.0008]), although similar to low-activity SLE patients. More infants who were small for gestational age were born to SLE than UCTD patients (33% versus 7% [P = 0.0005]), regardless of disease activity level.Pregnancies in women with UCTD managed by a rheumatologist have a high rate of pregnancy success and fewer risks than those in women with active SLE.

Cirrhosis is end-stage liver disease resulting from various etiologies and is a common cause of death worldwide. The progression from compensated to decompensated cirrhosis to acute-on-chronic liver failure (ACLF) is due to multiple factors, including continuation of alcohol use or continued exposure to other toxins, an imbalance of the gut microbiota (dysbiosis), increased gut permeability and a disrupted immune response. This disrupted immune response is also named cirrhosis-associated immune dysfunction, which is characterized by worsening systemic inflammation with concomitant immune paralysis, as liver disease deteriorates. This review highlights central immunologic events during the exacerbation of cirrhosis and characterizes the different immune cell populations involved therein.

BackgroundA rare subset of vitamin B6 responsive seizure disorders does not respond to pyridoxine, and requires the active form of vitamin B6, pyridoxal-5′-phosphate (PLP), to maintain seizure control. Patients with PLP-responsive seizures are dependent on chronic PLP treatment, yet no licensed PLP product is available. PLP food supplements, a product category regulated less stringently than medication, may prove of insufficient effectiveness and safety. Here we describe and discuss three patient scenarios which illustrate this conundrum.MethodsMedical and laboratory records were reviewed with retrospective extraction for three unrelated patients who suffered complications during treatment with PLP food supplements.Results– Two cases of PNPO deficiency and one case of PLP-dependent epileptic encephalopathy without a (genetic) diagnosis are reported. These patients are critically dependent on PLP for seizure control and have suffered complications due to insufficient quality of these food supplements during the course of treatment. Complications include the occurrence of seizures following the administration of suspected low quality PLP, inactive PLP due to light exposure, a PLP intoxication, resisting administration and post-administration vomiting as a result of the ingestion of large amounts of capsules per day.Conclusion– This case series illustrates that the reliance on food supplements as anti-seizure therapy is not without risk. The treatment of PLP-dependent seizures exemplifies that PLP is administered as medication, thus there is a clear need for licensed vitamin products of pharmaceutical quality.

Background and objective Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease with clinical characteristics that show geographic variations. However, these differences between regions have not been fully described; therefore, the objective of this study is to describe the clinical and sociodemographic characteristics of Cuban patients with SLE. Patients and methods 149 patients with SLE and 151 with other systemic autoimmune diseases were studied. Sociodemographic and clinical characteristics according on the criteria of the American College of Rheumatology of 1997 were identified. To evaluate the associations between clinical manifestations and SLE, a logistic regression analysis was performed; the odds ratio (OR) was calculated with its corresponding 95% confidence interval and the method of multiple correspondence analysis was also used. By an analysis of the configurations of frequency the typical combinations of criteria related to the patients with SLE were identified. Results The most frequent criteria in SLE were immunological disorders (85.2%). ANA positive (85.2%) arthritis (78.5%), photosensitivity (77.2%), and malar rash (61%). The renal involvement and immunological disorders criteria were the best (highest OR) at discriminating SLE patients. The combination of only three criteria (malar rash, positive ANA, and immunological disorder) could be enough to classify a homogeneous population. Conclusions This study enabled us to determine the main clinical characteristics of patients with SLE in Cuba. This information could be useful to improve the efficiency of SLE diagnosis and facilitate more specific treatments.

The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population. TAM expressing C1q correlate with T cell exhaustion and poor prognosis in numerous cancers. Herein, we discuss the plural roles of C1q in these macrophages and how it could drive cancer progression.

We herein report a patient with giant cell arteritis (GCA) who developed pneumatosis intestinalis (PI) while she was in a clinically sustained remission phase. A 79-year-old woman with GCA involving the thoracic aorta and its first branches to the posterior tibial arteries had been treated with high-dose prednisolone. Nine weeks after initiating treatment and while in clinically sustained remission with a normal CRP level, PI and pneumoperitoneum were incidentally found during scheduled positron emission tomography-computed tomography, which also revealed slight residual inflammation of GCA. This is a very rare case of PI complicated by GCA, and we discuss the possible relationships.

Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

Data are limited regarding the immune status of CD40 ligand (CD40L)–deficient carriers and hematopoietic stem cell transplantation (HSCT) outcomes using them as donors for CD40L-deficient patients. Therefore, we studied the immune profiles of 7 carriers, 4 of whom were HSCT donors for family members with CD40L deficiency, and we characterized their HSCT outcomes. Immunoglobulin profiles, CD4, CD8, circulating T-follicular helper (cTfh) cells, and regulatory T cells (Tregs) in carriers were comparable to those in healthy controls. CD40L expression in carriers ranged from 37% to 78%. cTfh cells from carriers expressed higher CD40L compared with total CD4 cells or the memory CD4 compartment, suggesting a potential advantage to CD40L-expressing cTfh cells. Tregs had minimal CD40L expression in carriers and healthy controls. So we postulated that HSCT using donors who were CD40L carriers may result in excellent immune reconstitution without immune dysregulation. Four CD40L-deficient patients underwent HSCT from carriers who had CD40L expression from 37% to 63%. All patients engrafted, achieved excellent immune reconstitution with lack of opportunistic infections, graft-versus-host disease, and immune dysregulation; stable CD40L expression mimicked that of donors 1 to 5 years after HSCT. Immunoglobulin independence was achieved in 3 of the 4 patients. We demonstrated higher CD40L expression in the cTfh compartment of carriers and excellent immune reconstitution using donors who were CD40L carriers in CD40L-deficient patients.

Background. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignant lymphoma with distinct characteristics. Patients with treatment failure after the standard immunochemotherapy have worse prognosis, which implies the necessity to uncover novel targets. The C-X-C chemokine receptor 4 (CXCR4) overexpression has been identified in several hematopoietic malignancies. However, the expression signatures and prognostic significance of CXCR4 in DLBCL associated with clinicopathological features remain unclear. Methods. Gene expression profiles of DLBCL were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, a meta-analysis with an integrated bioinformatic analysis was performed to assess the relationship between CXCR4 expression and clinicopathological features of DLBCL. Finally, experimental verification including immunohistochemical (IHC) staining and real-time quantitative PCR (qPCR) was carried out using patient samples. In vitro cell line viability tests were conducted using CXCR4 inhibitor WZ811. Results. DLBCL patients with activated B-cell-like (ABC) subtype have higher expression level of CXCR4 with worse survival. Differential expressed genes in the CXCR4-upregulation group were enriched in canonical pathways associated with oncogenesis. DLBCL with CXCR4 upregulation had lower degree of CD8+ T cell infiltration. TIMER analysis demonstrated that the CXCR4 expression was positively correlated with the expression of CD5, MYC, NOTCH1, PDCD1, CD274, mTOR, FOXO1, and hnRNPA2B1 in DLBCL. IHC study in patient samples showed the positive correlation between CXCR4 and nongerminal center B-cell (non-GCB) subtype and mTOR expression. Meanwhile, quantitative polymerase chain reaction results revealed that high CXCR4 mRNA level was correlated to double-hit DLBCL. Finally, cell viability test showed that WZ811 exerted antiproliferation effect in DLBCL cell lines in a dose-dependent manner. Conclusion. CXCR4 was upregulated in ABC-DLBCL associated with worse prognosis. Our analysis predicted CXCR4 as a potential target for DLBCL treatment, which may serve as an inhibitor both on BCR signaling and nuclear export warranting further investigation in clinical trials.

Purpose. This study was conducted to characterize the expression level of peripheral blood toll-like receptors 9 (TLR9), nuclear factor kappa-B protein 65 (NF-κB p65), and myeloid differentiation factor88 (MyD88) of active systemic lupus erythematosus (SLE) and analyse their clinical significance. Methods. The prospective cohort study enrolled 30 active SLE patients (SG1 group), 30 stable SLE patients (SG2 group), and 20 healthy individuals (RG group) in the First Affiliated Hospital of Hainan Medical University between January 2018 and June 2020. All SLE patients were treated with methylprednisolone tablets. Quantitative polymerase chain reaction (qPCR) was used to determine the levels of TLR9, MyD88, and NF-κB p65 in the peripheral blood mononuclear cell (PBMC). ELISA was adopted for the determination of serum interleukin (IL-6) and tumor necrosis factor-α (TNF-α). Results. Patients in SG1 showed the highest mRNA levels of TLR9, MyD88, and NF-κB p65, followed by SG2, and then RG. SG1 had the highest serum levels of IL-6 and TNF-α, followed by SG2 and RG. The level of TLR9 was positively correlated with the SLE disease activity index (SLEDAI) and negatively correlated with complement component 3 (C3) and complement component 4 (C4). MyD88 and NF-κB p65 were positively correlated with SLEDAI. Conclusion. Compared with a healthy status, SLE induces an increase in TLR9, MyD88, NF-κB p65, IL-6, and TNF-α levels, and the activation of the TLR9-MyD88-NF-κB p65 signal path was associated with the pathogenesis of SLE.

Intestinal serotonergic system is a key modulator of intestinal homeostasis; however, its regulation is still unclear. Toll-like receptor 9 (TLR9), an innate immune receptor, detects different external agents in the intestine, preserving intestinal integrity. Since little is known about TLR9 role in the intestine, our aim was to address the potential regulation between TLR9 and intestinal serotonergic system. Caco-2/TC7 cell line and intestinal tract of Tlr9−/− mice were used in this study. Serotonin uptake studies were performed, and molecular expression of different serotonergic components was analyzed by western blot and real-time PCR. Our results show that TLR9 activation inhibits serotonin transporter activity and expression, involving p38/MAPK and ERK/MAPK intracellular pathways, and reciprocally, serotonin increases TLR9 expression. Supporting this interaction, serotonin transporter, serotonin receptors and serotonin producer enzymes were found altered in intestinal tract of Tlr9−/− mice. We conclude that TLR9 could contribute to intestinal homeostasis by modulation of intestinal serotonergic system.

Although there is a high curability rate with rituximab chemotherapy, approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) develop disease relapse or primary-refractory lymphoma. The prognosis of HIV+ DLBCL patients is even worse with limited therapeutic options. The case is presented of a 28-year-old man who was diagnosed with HIV-DLBCL, refractory to rituximab-based chemo-immunotherapies and radiotherapy before and maintained a pathologically complete regression with the infusion of haplotype-matched invariant NK T cells and anti-CD20 antibody. His abdominal mass kept shrinking during the period of follow-up without relapse to date. A combination of haplotype-matched invariant NK T cells was likely to reinvigorate the efficacy of anti-CD20 antibody and may offer a viable treatment option for refractory DLBCL patients.Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent types of lymphoid cancer. The prognosis of relapsed/refractory DLBCL patients has been dismal with resistance to rituximab-based chemo-immunotherapy. The combination of effective cells with rituximab might improve clinical response by enhancing antibody-dependent cytotoxicity. The authors reported the case of a 28-year-old man diagnosed with HIV-DLBCL, refractory to 3 lines of rituximab-based chemo-immunotherapies and radiotherapy before, and who received 6 experimental infusions of haplotype-matched invariant NK T cells combined with anti-CD20 antibody. The lesion on radiological examination was partially regressed after cycle 3 and cycle 6. The pathological examination, performed 4 weeks after cycle 6, suggested pathologically complete regression. The mass was completely regressed on CT scanning without relapse to date. A combination of invariant NK T cells and anti-CD20 antibody may offer a viable treatment option for relapsed/refractory DLBCL patients for whom rituximab chemotherapy was not effective.

Background: Avascular necrosis (AVN) is a major cause of disability in systemic lupus erythematosus (SLE) patients which directly affects the functionality and quality of life. Total hip arthroplasty (THA) is indicated for severe cases with major disability and severe pain. It is still debatable if SLE is an independent risk factor for poor outcome in THA or not. Aim of the work: To evaluate the result of THA for AVN of the femur head in SLE patients. Patients and methods: 22 THAs were performed in 20 SLE patients and were compared with the results of 25 hips of 22 patients who had THA due to AVN with non-SLE conditions. All patients were followed up after the surgery at 6 weeks, 3, 6 and 12 months post-operatively, and then yearly for functional and radiological outcomes. Results: The Harris hip score (HHS) increased from a preoperative average of 26 points to 93.52 at the most recent follow-up. In the control group, the mean HHS was 26 preoperatively and 95.52 postoperatively at the last follow-up. Visual analog scale for pain (VAS pain) decreased from 8 in SLE and 6 in the non-SLE group to 2 and 1 respectively. No significant difference was found between SLE patients and non-SLE patients regarding complications except for more chest infections in the SLE group. No mortality was recorded in both groups in the postoperative follow-up period of a mean of thirty months. Conclusion: THA outcome is as favorable in AVN patients with SLE as in non-SLE.

Data on the incidence and severity of radiation-induced toxicity in patients with systemic and/or cutaneous lupus erythematosus (SLE/CLE) are very limited. After reporting the case of a patient who experienced major toxicity and CLE flare in the irradiated area following breast irradiation, we conducted a comprehensive literature review of available data in this setting. The few retrospectives studies which have evaluated both the risk of toxicity in SLE/CLE patients and/or the potential induction or reactivation of SLE/CLE with radiotherapy have not shown differences between SLE/CLE patients and controls. Several other factors such as concurrent chemotherapy, a particular genetic background, or lupus treatments (essentially hydroxychloroquine) can explain severe radiation-induced toxicity. Therefore, patients with SLE/CLE should be irradiated like patients without SLE/CLE, with close monitoring during radiotherapy if other risk factors exist. Further studies examining a larger number of patients would probably allow a better understanding of the radiosensitivity of these patients.

Non-Hodgkin lymphoma (NHL) is a disease of older adults, with a median age at diagnosis of 67 years. Treatment in older adults with NHL is challenging. The aging process is associated with a decline in functional reserve that varies among individuals, and results in an increasing risk of treatment-related toxicity and mortality. Chronological age and performance status fail to capture the multidimensional and heterogeneous nature of the aging process. A geriatric assessment (GA) screens multiple geriatric domains and provides a more accurate assessment of functional reserve. Several abbreviated GA tools have been developed for use in oncology clinics and help identify patients at high risk for chemotherapy-related toxicity and mortality. In this review, we explore GA tools validated for use in patients with NHL. We discuss the evidence behind GA–guided treatment in NHL and present a suggested approach to assessing frailty in this patient population.

Lymphomas of the breast are rare neoplasms that arise from breast lymphoid tissue and are characterised by neoplastic B or T cells. Breast lymphomas arising from B cells include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, extra-nodal marginal zone lymphoma and Burkitt lymphoma. Anaplastic large cell lymphoma (ALCL) is of a T cell origin and both anaplastic lymphoma kinase (ALK)-positive and ALK-negative presentations have been noted in the breast. In addition, there is a more recently identified presentation of ALK-negative ALCL that arises around textured breast implants and is usually confined to a periprosthetic fibrous capsule. Here, we discuss the clinical presentations, histological and immunohistochemical features and treatment options for each type of primary breast lymphoma. We hope that this review will highlight the importance of the timely and accurate diagnosis of breast lymphoma in order to tailor the most appropriate treatment. We also wish to raise awareness of the breast implant-associated lymphomas, with the goal of stimulating work that will aid our understanding of their epidemiology and pathogenesis.

In recent decades, a dramatic rise has been observed in the prevalence of obesity in childhood and adolescence, along with an increase in fetal microsomia rates. The increased risk of obesity during this key period in development negatively affects the health of the individual later in life. Immune cells residing and recruited to white adipose tissue have been highlighted as important factors contributing to the pathogenesis of childhood obesity. Immune dysfunction in the context of obesity begins early in childhood, which is different from the pathological characteristics and influencing factors of adipose immunity in adults. Here, we explore the current understanding of the roles of childhood and early life events that result in high risks for obesity by influencing adipose tissue immune dysfunction under the pathological condition of obesity. Such knowledge will help in determining the mechanisms of childhood and early life obesity in efforts to ameliorate chronic inflammation-related metabolic diseases.

A 78-year-old man was treated with Bortezomib, Lenalidomide, and Dexamethasone, for multiple myeloma. Two years after the start of treatment, the patient came to our department with a complaint of gross hematuria. Cystoscopy revealed a tumor on the left wall of the bladder. Urine cytology was negative. Magnetic resonance imaging (MRI) of the lower abdomen showed a slightly high signal on the T2-weighted image, indicating an intravesical mass lesion invading outside the bladder. Contrast-enhanced computed tomography (CT) also showed an intravesical mass and enlarged left external iliac lymph node swelling. Transurethral resection of bladder tumor was performed. The resection specimen showed tumor cells. The pathological examination revealed CD138 (+) and light-chain restriction. The patient was diagnosed with plasmacytoma. The patient was treated with radiation therapy for plasmacytoma of the bladder and surrounding lymph nodes, and then with daratumumab and dexamethasone for multiple myeloma for one year; however, the patient died because of worsening of multiple myeloma.

Research on newborn immunity has revealed the importance of cell ontogeny, feto-maternal tolerance, and the transfer of maternal antibodies. Less is known about postnatal adaptation to environmental exposures. The microbiome and its importance for health have been extensively studied, but it remains unclear how mutually beneficial relationships between commensal microbes and human cells first arise and are maintained throughout life. Such immune-microbe mutualism, and perturbations thereof, is most likely a root cause of increasing incidences of immune-mediated disorders such as allergies and autoimmunity across many industrialized nations during the past century. In this Review, I discuss our current understanding of immune development and propose that mismatches among ancestral, early-life, and adult environments can explain perturbations to immune-microbe interactions, immune dysregulation, and increased risks of immune-mediated diseases.

CD4

COVID-19 has had a calamitous impact on the global community. Apart from at least 6 M deaths, hundreds of millions have been infected and a much greater number have been plunged into poverty. Vaccines have been effective but financial and logistical challenges have hampered their rapid global deployment. Vaccine disparities have allowed the emergence of new SARS-CoV-2 variants including delta and omicron, perpetuating the pandemic.The immunological response to SARS-CoV-2 is now better understood. Many of the clinical manifestations of severe disease are a consequence of immune dysregulation triggered by the virus. This may explain the lack of efficacy of antiviral treatments, such as convalescent plasma infusions, given later in the disease.T cells play a crucial role in both the outcome of COVID-19 as well as the protective response to vaccines. Vaccines do not prevent infection but reduce the risk of a chaotic and destructive cellular immune response to the virus. Severe COVID-19 should be considered a virus-induced secondary immune dysregulatory disorder of cellular immunity, with broad host susceptibility. This perspective of COVID-19 will lead to better diagnostic tests, vaccines, and therapeutic strategies in the future.

Objective. Concurrent follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) (defined as FL/DLBCL) have been considered an important pathological feature in cell lymphoma. However, clinicopathological information and prognostic factors in these cases are scarce. The aim of this study was to construct a prediction index to compare with traditional prognostic models. Methods. Retrospectively enrolled, previously untreated FL/DLBCL ( n = 121 ) patients, as well as those with pure FL 1–3a ( n = 471 ), were assessed. De novo DLBCL ( n = 529 ) were used as controls. Kaplan–Meier curves were plotted to compare the outcomes among the three groups. Multivariate analysis identified risk factors associated with overall survival (OS) in FL/DLBCL patients. A clinicopathological prognosis index (CPPI) was developed to predict OS based on the Cox proportional hazards model. Results. The outcomes of FL/DLBCL patients were intermediate between pure FL 1–3a and de novo DLBCL patients, with a 5-year PFS of 70%, 59%, and 48% ( P < 0.05 ) and 5-year OS of 80%, 70% and 60% ( P < 0.05 ), respectively. Cox regression analysis showed that the prognostic factors of OS for FL/DLBCL patients included FL grade, cell of origin, and Ann Arbor stage. A nomogram and clinicopathological prognostic index (CPPI) were developed to predict the OS for FL/DLBCL patients based on these factors. The area under the curve (AUC) of the CPPI for 3- and 5-year OS prediction was 0.782 and 0.860, respectively. This was superior to that of the International Prognostic Index (IPI), Follicular Lymphoma International Prognostic Index (FLIPI), and FLIPI2 in the 0.540–0.819 ( P < 0.01 ) range. Conclusions. A valid OS estimation in FL/DLBCL patients, using the recommended CPPI, may be useful in routine clinical practice.

Pemphigus is a chronic blistering disorder caused by autoantibodies that target desmosomal proteins in the epidermis. Acantholysis may be absent, and pemphigus may present only with spongiosis and vesiculation, thereby leading to a misdiagnosis of eczema. Herein, we conducted a retrospective, observational, single-center study to establish a pattern of spongiosis in cases of pemphigus confirmed by direct immunofluorescence. Immunopathologically diagnosed pemphigus specimens from 2001 to 2020 were retrieved, and specimens with spongiosis were analyzed for the following features: vesiculation, acantholysis, spongiosis, inflammatory cells in the epidermis, and inflammation in the dermis. Cases of spongiotic dermatitis were used as control. Out of 99 immunopathologically diagnosed pemphigus specimens, 41 samples with spongiosis were identified. About one quarter of the specimens did not have acantholysis. Spongiosis in the middle to lower thirds of the perilesional epidermis (p = 0.030), exocytosis with either neutrophils or eosinophils (p = 0.016), dermal infiltrates composed of lymphocytes, eosinophils, and neutrophils (p = 0.012), and absence of Langerhans cell microabscesses (p < 0.001) were more common in pemphigus than control. Spongiosis in pemphigus may mimic eczema in patients without acantholysis. The subtle histological findings in this study provide diagnostic clues and suggest that further immunofluorescence should be performed to confirm pemphigus diagnosis.

To evaluate the application of the EULAR/ACR-2019 criteria to monogenic lupus patients and compare its performance against the SLICC-2012 criteria.In a multicenter retrospective cohort study, consecutive patients with monogenic lupus from three tertiary lupus clinics were enrolled. The diagnosis of monogenic lupus was based on the expert physician's opinion or fulfilling the SLICC-2012 criteria. All enrolled patients had genetic variants. A control group of sporadic childhood SLE (cSLE) and non-SLE patients, were included. A descriptive data analysis was conducted, and the EULAR/ACR-2019 and SLICC-2012 criteria were applied to both groups.Forty-nine patients with monogenic lupus with a median age at diagnosis of 6.0 (IQR 3.0-10.8) years and 104 controls (55 patients with cSLE and 49 non-lupus patients with a median age at diagnosis of 10.0 and 5.0 respectively) were included. Forty-four (89.8%) patients with monogenic lupus fulfilled the EULAR/ACR-2019 with a mean score of 22.3±8.9. The most frequent domains were immunologic (93.9%), musculoskeletal and renal (each 57.1%), and mucocutaneous (55.1%). Fifty-four (98.2%) cSLE patients and six (12.2%) non-lupus patients met the EULAR/ACR-2019 criteria with a mean score of 22.5±9.2 and 8.5±5.2, respectively. The sensitivity of the EULAR/ACR-2019 criteria in monogenic lupus was 89.9% (95% CI: 78.3-90.2), while the specificity was 87.6% (95% CI: 75.2-88.7).This is the first and largest cohort of monogenic lupus patients testing the performance of the 2019-EULAR/ACR criteria. It efficiently classifies monogenic lupus patients, irrespective of the underlying genetic variants. Further studies are needed before these criteria are adopted worldwide. Key Points • Typically, patients with monogenic lupus have early onset severe disease, especially with mucocutaneous manifestations and a strong family history of SLE. • Monogenic lupus is a distinctive entity and might differ from the sporadic childhood SLE. • Our study includes a large multinational cohort of monogenic lupus with heterogeneous phenotypic features and underlying genetic variants. • Our study demonstrates that the EULAR/ACR-2019 criteria efficiently classified monogenic lupus patients, irrespective of the diversity of the underlying genetic variants.