Ancestry-based differences in the immune system are associated with lupus severity

Systemic lupus erythematosus (SLE) affects 1 in 537 of African American (AA) women, which is >2-fold more than European American (EA) women. AA patients also develop the disease at a younger age, have more severe symptoms, and a greater chance of early mortality. We used a multi-omics approach to uncover ancestry-specific immune alterations in SLE patients and healthy controls that may contribute to disease disparities. Cell composition, signaling, and epigenetics were evaluated by mass cytometry; droplet-based single cell transcriptomics and paired proteogenomics (scRNA-Seq/scCITE-Seq). Soluble mediator levels were measured in plasma and stimulated whole blood. Toll-like receptor (TLRs) pathways are activated by vaccination and microbial infection, and are also key drivers of autoimmune disease. We observed enhanced TLR3/4/7/8/9-related gene expression in immune cells from AA versus EA SLE patients. TLR7/8/9 and IFNα phospho-signaling responses were heightened even in immune cells from healthy AA versus EA controls. TLR stimulation of healthy AA and EA immune cells recapitulated the distinct ancestry-associated SLE immunophenotypes. Thus, healthy individuals show ancestry-based differences in innate immune pathways that could influence the course and severity of lupus and other diseases.

Innate and Adaptive Immunity Imbalance With Severe COVID-19 Pneumonia in Children and Adults

Introduction: Little is known about the laboratory and radiological characteristics and clinical significance of peripheral immune alterations in patients with coronavirus disease 2019 (COVID-19). This study aims to clarify these aspects in children and adults with COVID-19.Methods: In this consecutive pilot study, COVID-19 patients with the confirmed pneumonia and real-time RT-PCR were recruited prospectively in June 2020. The clinical, chest CT, and laboratory features, such as lymphocyte subpopulations, were analyzed for each individual.Results: Forty confirmed COVID-19 patients, 11 severe children, 12 severe adults, and 17 critical adult patients, besides 20 healthy pediatrics and 14 healthy adults as controls, were enrolled prospectively. Adult patients, especially critical ones, had a much higher prevalence of laboratory and chest CT abnormalities. Data regarding immune cell subsets in children patients, compared with matched controls, had higher CD3+ CD8+ T cells (p = 0.004) and lower CD4+/CD8+ ratio (p = 0.042), while adult patients, compared with matched controls, had lower CD14+ monocytes (p = 0.032). Adult patients were also categorized as experiencing critical or severe illness on admission and, compared with severe patients, had lower total lymphocytes (p < 0.047), CD3+ T-lymphocytes (p < 0.002), and CD3+ CD8+ T cells (p = 0.001) and, on the other hand, had higher CD3+ CD4+ T cells (p = 0.012) and CD4+/CD8+ ratio (p = 0.003). Non survived adults, compared with survived patients, had significantly lower CD3+ T-lymphocyte (p = 0.005).Conclusion: Unlike adult patients, who compared with matched controls and had more comorbidities, higher frequency of severe clinical symptoms, laboratory abnormalities, and immune cells alteration, clinical manifestations of COVID-19 in children (compared with matched controls) were relatively mild, and fewer clinical complications were seen either, perhaps because of a milder inflammatory response following their peripheral innate and adaptive immune cell alteration pattern.

The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy

Successful pregnancy requires an immunological shift with T helper CD4+ bias based on disbalance Th1/Th17 versus Th2/T regulatory (Tregs) required to induce tolerance against the semi-allogeneic fetus and placenta and to support fetal growth. Considered a pregnancy-specific hypertensive disorder, pre-eclampsia is characterized by multifaceted organ involvement related to impaired maternal immune tolerance to paternal antigens triggered by hypoxic placental injury as well as excessive local and systemic anti-angiogenic and inflammatory factor synthesis. Both systemic and local Th1/Th2 shift further expands to Th17 cells and their cytokines (IL-17) complemented by suppressive Treg and Th2 cytokines (IL-10, IL-4); alterations in Th17 and Tregs cause hypertension during pregnancy throughout vasoactive factors and endothelial dysfunction, providing an explanatory link between immunological and vascular events in the pathobiology of pre-eclamptic pregnancy. Apart from immunological changes representative of normotensive pregnancy, lupus pregnancy is generally defined by higher serum pro-inflammatory cytokines, lower Th2 polarization, defective and lower number of Tregs, potential blockade of complement inhibitors by anti-phospholipid antibodies, and similar immune alterations to those seen in pre-eclampsia. The current review underpins the immune mechanisms of pre-eclampsia focusing on local (placental) and systemic (maternal) aberrant adaptive and innate immune response versus normotensive pregnancy and pregnancy in systemic autoimmune conditions, particularly lupus.

Immunity and inflammation: the neglected key players in congenital heart disease?

Although more than 90% of children born with congenital heart disease (CHD) survive into adulthood, patients face significantly higher and premature morbidity and mortality. Heart failure as well as non-cardiac comorbidities represent a striking and life-limiting problem with need for new treatment options. Systemic chronic inflammation and immune activation have been identified as crucial drivers of disease causes and progression in various cardiovascular disorders and are promising therapeutic targets. Accumulating evidence indicates an inflammatory state and immune alterations in children and adults with CHD. In this review, we highlight the implications of chronic inflammation, immunity, and immune senescence in CHD. In this context, we summarize the impact of infant open-heart surgery with subsequent thymectomy on the immune system later in life and discuss the potential role of comorbidities and underlying genetic alterations. How an altered immunity and chronic inflammation in CHD influence patient outcomes facing SARS-CoV-2 infection is unclear, but requires special attention, as CHD could represent a population particularly at risk during the COVID-19 pandemic. Concluding remarks address possible clinical implications of immune changes in CHD and consider future immunomodulatory therapies.

A specific structure and high richness characterize intestinal microbiota of HIV-exposed seronegative individuals

Intestinal microbiota facilitates food breakdown for energy metabolism and influences the immune response, maintaining mucosal homeostasis. Overall, HIV infection is associated with intestinal dysbiosis and immune activation, which has been related to seroconversion in HIV-exposed individuals. However, it is unclear whether microbiota dysbiosis is the cause or the effect of immune alterations and disease progression or if it could modulate the risk of acquiring the HIV infection. We characterize the intestinal microbiota and determine its association with immune regulation in HIV-exposed seronegative individuals (HESN), HIV-infected progressors (HIV+), and healthy control (HC) subjects. For this, feces and blood were collected. The microbiota composition of HESN showed a significantly higher alpha (p = 0.040) and beta diversity (p = 0.006) compared to HC, but no differences were found compared to HIV+. A lower Treg percentage was observed in HESN (1.77%) than HC (2.98%) and HIV+ (4.02%), with enrichment of the genus Butyrivibrio (p = 0.029) being characteristic of this profile. Moreover, we found that Megasphaera (p = 0.017) and Victivallis (p = 0.0029) also are enriched in the microbiota composition in HESN compared to HC and HIV+ subjects. Interestingly, an increase in Succinivibrio and Prevotella, and a reduction in Bacteroides genus, which is typical of HIV-infected individuals, were observed in both HESN and HIV+, compared to HC. Thus, HESNs have a microbiota profile, similar to that observed in HIV+, most likely because HESN are cohabiting with their HIV+ partners.

Tonsillectomy, appendectomy and splenectomy: sequels and malignant evolution

The excision of secondary lymphoid organs might not be harmless. Although the procedure itself, is less and less performed presently, infectious sequels in total splenectomy might occur and are possibly fatal. Among further complications, thromboembolic and immune alterations should also be expected. The most debatable of consequences, probably associated with an immune adjustment, concerns the development of malignancies. Considering post-splenectomy tumors, discrepancies emerge between their occurrence in humans, and their consequent protective effect in experimental animals. It is recommended that surgeons aspire at preserving as much of lymphoid tissues a feasible, when performing such resections.

Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk

Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

Serum Proteomic Analyses Suggest That the HMGB1 and Other Inflammatory Pathways Are Operational in MBL and Are Less in Overt CLL

Background. CLL-like monoclonal B-ceII lymphocytosis (MBL) is considered a requisite precursor of CLL, with 1-2% of subjects annually progressing to CLL requiring therapy. The role of immune alterations leading to and operating in MBL and controlling progression to CLL is not well characterized. Since an increased frequency of immune-related conditions associated with immune dysfunction exists prior to CLL diagnosis (Landgren et al, Br J Haematol 2007 and Blood 2007; Andersen et al, Leukemia 2020), immune alterations likely exist in MBL. We have examined the serum protein profiles of MBL and CLL in search of clues linking immune dysfunction with malignant transformation. Objectives. 1. Characterize the serum proteomic profiles of MBL individuals, IGHV-mutated CLL (M-CLL) and IGHV-unmutated CLL (U-CLL) patients, and age-matched healthy controls (HC). 2. Compare the serum proteomic profiles between the groups. 3. Assess the effect of IGHV mutation status on serum proteomic profiles in CLL. Methods. A total of 12 MBL, 12 M-CLL, 12 U-CLL and 12 age-matched HC were studied. Patients were cared for at Northwell Health, New York (n=25) and Hospital del Mar, Barcelona (n=11). All patients were treatment naive except for one U-CLL patient who was treated one year beforehand. Serum samples were collected, and their protein levels measured employing SOMAmers (modified single-stranded DNA aptamers; SomaLogic) to quantify relative levels of 1,310 proteins. P-values <0.05 were used to define significantly different protein levels between groups. Ingenuity Pathway Analysis (IPA; QIAGEN) was employed to evaluate potential protein interactions and pathways. IPA pathways with P-value <0.05 and Z-score ≥2 or ≤-2 were considered to be activated or inhibited, respectively. Results. Overall, the levels of 862 proteins differed significantly between groups: MBL vs. HC: 10 downregulated (d) and 24 upregulated (u); M-CLL vs. HC: 206d and 6u; U-CLL vs. HC: 54d and 40u; M-CLL vs. MBL: 384d and 5u; U-CLL vs. MBL: 74d and 24u; and M-CLL vs. U-CLL: 35d and 0u. IPA highlighted a role for the pro-inflammatory HMGB1 pathway in several comparisons. First, an activated HMGB1 pathway was predicted in MBL compared to HC, together with activation of phagocytes, and an inhibition of the systemic immune suppressor TGF-β. Second and consistent with the former, U-CLL patients displayed an activated HMGB1 pathway compared to HC, along with other signs of immune stimulation (activated NFkB and Th1 pathways, maturation of dendritic cells, and inhibition of TGF-β) and leukemic progression (activated progression of tumor, and leukocyte extravasation). Third and contrary to the above, the HMGB1 pathway was inhibited when comparing M-CLL to HC, in line with a global immune suppression signature (inhibited PRR, GM-CSF, FcεRI, IL1, IL8, TNF, Th1, STAT3 and NFkB pathways, in addition to inhibited cell movement, viability and activation). Notably, inhibition of immune pathways was predicted for both M-CLL and U-CLL compared to MBL (diminished TNF and IL6 signaling, and reduced cell movement), although the greatest differences were seen for M-CLL vs. MBL comparison, including blockade of the HMGB1 pathway in M-CLL. Finally, the M-CLL vs. U-CLL comparison suggested inhibited INFγ, IL2, IL3, IL4, NFkB, and decreased T lymphocyte stimulation and movement of tumor cells in M-CLL patients. Conclusions. An increased pro-inflammatory signature with involvement of the HMGB1 pathway was identified in MBL and U-CLL compared with HC, whereas the opposite was seen for M-CLL. Since MBL most often exhibit mutated IGHV (91% of cases in our cohort), these findings suggest immune stimulation as a characteristic feature in the pre-leukemic and U-CLL leukemic stage that surprisingly is not operative in M-CLL. Consistent with this, M-CLL displayed a global immune suppression (HMGB1 pathway inhibition), whereas U-CLL exhibited signs of immune stimulation (HMGB1 pathway activation) compared to HC which may relate to distinct capabilities of the two subtypes to interact with the microenvironment. Lastly, the increased inflammatory signature identified in MBL, which are mainly IGHV-mutated, was lessened in CLL, mainly in M-CLL patients. This is consistent with a decreased influence of immune imbalance and the HMGB1 pathway associated with IGHV-mutated clonal expansions. Acknowledgments. GB is supported by a grant from Fundación Alfonso Martín Escudero. Disclosures Allen: Alexon: Research Funding; Bristol Myers Squibb: Other: Equity Ownership; C4 Therapeutics: Other: Equity Ownership; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

The immune microenvironment is a critical driver and regulator of leukemic progression and hematological disease. Recent investigations have demonstrated that multiple immune components play a central role in regulating hematopoiesis, and dysfunction at the immune cell level significantly contributes to neoplastic disease. Immune cells are acutely sensitive to remodeling by leukemic inflammatory cytokine exposure. Importantly, immune cells are the principal cytokine producers in the hematopoietic system, representing an untapped frontier for clinical interventions. Due to a proinflammatory cytokine environment, dysregulation of immune cell states is a hallmark of hematological disease and neoplasia. Malignant immune adaptations have profound effects on leukemic blast proliferation, disease propagation, and drug-resistance. Conversely, targeting the immune landscape to restore hematopoietic function and limit leukemic expansion may have significant therapeutic value. Despite the fundamental role of the immune microenvironment during the initiation, progression, and treatment response of hematological disease, a detailed examination of how leukemic cytokines alter immune cells to permit, promote, or inhibit leukemia growth is lacking. Here we outline an immune-based model of leukemic transformation and highlight how the profound effect of immune alterations on the trajectory of malignancy. The focus of this review is to summarize current knowledge about the impacts of pro- and anti-inflammatory cytokines on immune cells subsets, their modes of action, and immunotherapeutic approaches with the potential to improve clinical outcomes for patients suffering from hematological myeloid malignancies.