Generation of plasma cells and CD27<sup>−</sup>IgD<sup>−</sup> B cells during hantavirus infection is associated with distinct pathological findings

Kerkman, Priscilla F; Dernstedt, Andy; Tadala, Lalitha; Mittler, Eva; Dannborg, Mirjam; Sundling, Christopher; Maleki, Kimia T.; Tauriainen, Johanna; Tuiskunen-Bäck, Anne; Byström, Julia Wigren; Ocaya, Pauline; Thunberg, Therese; Jangra, Rohit K.; Roman-Sosa, Gleyder; Guardado-Calvo, Pablo; Rey, F.A.; Klingström, Jonas; Chandran, Kartik; Puhar, Andrea; Ahlm, Clas; Forsell, Mattias N.E.

doi:10.1002/cti2.1313

Cited by 7 publications

(4 citation statements)

References 59 publications

(134 reference statements)

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“…We then assessed the distribution of switched memory B cells (CD19 + CD20 + CD27 + IgD - ), unswitched memory B cells (CD19 + CD20 + CD27 + IgD + ), naïve B cells (CD19 + CD20 + CD27 - IgD + ), and double negative (DN) B cells (CD19 + CD20 + CD27 - IgD - ). The frequencies of these populations in the control group were similar to previously reported findings ( 19 ), whereas the MS patients had reconstituted a predominantly naïve repertoire during RTX treatment interruption ( Figure 4C ).…”

Section: Resultssupporting

confidence: 89%

“…A similar difference was noted for S-specific unswitched memory B cells and we could also demonstrate that patients had a higher frequency of antigen-specific DN B cells than healthy controls at four weeks post a second BNT162b2 dose ( Figure 4D ). We have previously shown that B cells downregulate the complement regulatory protein DAF upon BCR engagement, and that DN B cells in circulation may reflect ongoing B cell responses in lymphoid organs ( 19 , 20 ). We found that patients had increased frequencies of DAF - cells in all B cell populations except for switched memory B cells one week after the second dose ( Figure 4E ).…”

Section: Resultsmentioning

confidence: 99%

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Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

et al. 2023

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Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

et al. 2023

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“…The cells showed reduced BCR signaling and antibody production upon stimulation, leading to the thought that the B cells were anergic or exhausted (39). Other infections where B cells with a CD21 lo CD27 lo IgD − phenotype are observed to expand are hepatitis C virus (HCV) (42,43), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (44)(45)(46), hantavirus infection (47) tuberculosis (48), and possibly others.…”

Section: Alternative B Cell Differentiation In Disease and Vaccinationmentioning

confidence: 99%

Alternative B Cell Differentiation During Infection and Inflammation

2022

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Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B cell activation and differentiation to long-lived plasma cells and memory B cells. For many viral or bacterial infections, a single encounter is sufficient to induce such responses. In malaria, the induction of long-term immunity can take years of pathogen exposure to develop, if it occurs at all. This repeated pathogen exposure and suboptimal immune response coincide with the expansion of a subset of B cells, often termed atypical memory B cells. This subset is present at low levels in healthy individuals as well but it is observed to expand in an inflammatory context during acute and chronic infection, autoimmune diseases or certain immunodeficiencies. Therefore, it has been proposed that this subset is exhausted, dysfunctional, or potentially autoreactive, but its actual role has remained elusive. Recent reports have provided new information regarding both heterogeneity and expansion of these cells, in addition to indications on their potential role during normal immune responses to infection or vaccination. These new insights encourage us to rethink how and why they are generated and better understand their role in our complex immune system. In this review, we will focus on recent advances in our understanding of these enigmatic cells and highlight the remaining gaps that need to be filled.

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“…32,44,45 Peripheral NK cells show signs of strong activation and proliferation in the acute phase of HFRS. [46][47][48][49] B and T cells are highly expanded in the circulation of HFRS and HPS patients, with concomitant elevated levels of CD8 + T cells in the respiratory airways, 36,[50][51][52][53][54] . Mucosa-associated invariant T (MAIT) cells were recently shown to be reduced but highly activated in circulation during PUUV-caused HFRS.…”

Section: Introductionmentioning

confidence: 99%

Innate lymphoid cells are activated and their levels correlate with viral load in patients with Puumala hantavirus caused hemorrhagic fever with renal syndrome

García

Tauriainen

et al. 2022

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BackgroundInnate lymphoid cells (ILCs) are involved in immunity and homeostasis but, except for natural killer (NK) cells, their role in human viral infections is not well known. Puumala virus (PUUV) is a hantavirus that causes the acute zoonotic disease hemorrhagic fever with renal syndrome (HFRS). HFRS is characterized by strong systemic inflammation and NK cells are highly activated in HFRS, suggesting that also other ILCs might be responding to infection.MethodsHere we phenotypically analyzed peripheral ILCs in acute and convalescent PUUV-infected HFRS patients. Additionally, plasma levels of soluble factors and viral load were analyzed.FindingsOverall, the frequencies of NK cells and naïve ILCs were reduced while the frequency of ILC2, in particular the ILC2-lineage committed c-Kitlo ILC2 subset, was increased during acute HFRS. Interestingly, we observed a negative correlation between viral load and frequencies of both NK and non-NK ILCs in acute HFRS. Phenotypically, ILCs displayed an activated profile with increased proliferation, and showed altered expression of several homing markers during acute HFRS. In line with the observation of activated ILCs, plasma levels of inflammatory proteins, including the ILC-associated cytokines interleukin (IL)-13, IL-23, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), were elevated during acute HFRS.InterpretationThese findings indicate a general involvement of ILCs in response to human hantavirus infection. Further, this constitutes the first comprehensive study of ILCs in a hantavirus-caused disease, aiding in further understanding the role of these cells in disease pathogenesis and in human viral infections in general.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.RESEARCH IN CONTEXTEvidence before this studyInnate lymphoid cells (ILCs) include a broad range of innate cell subsets involved, among other functions, in early response to infections. Natural killer (NK) cells have been broadly characterized in human viral infections, but much less is known in such context about other more recently discovered ILCs. Puumala virus is one of the causative agents of hemorrhagic fever with renal syndrome (HFRS), an acute zoonotic disease characterized by systemic inflammation. No current treatment or vaccines are available to date for hantavirus-caused diseases and pathogenesis is still not fully understood. A PubMed search up until April 2022 using a combination of the terms virus, Puumala virus, hantavirus, HFRS, ILCs, and NK cells shows that while studies have been performed characterizing NK cells in HFRS, no studies are available on the rest of ILCs in hantavirus-caused diseases, which in addition have been studied in only a handful of human viral infections.Added value of this studyIn this study we thoroughly characterized the ILC landscape in circulation and its milieu in acute and convalescent Puumala-infected HFRS patients. We found that the frequency of NK cells and other ILC subsets was altered in the acute HFRS patients as compared to convalescent HFRS patients and control individuals, with a decrease in NK cells and naïve ILCs, and an increase in ILC2. In particular the ILC2-lineage committed c-Kitlo ILC2 subset was found increased. Total ILCs showed increased levels of activation and proliferation, and signs of altered migration patterns in acute HFRS patients. The finding of elevated levels of several soluble inflammatory proteins associated with ILCs in acute HFRS patients further suggests an implication of ILCs in HFRS. Moreover, an association between the frequency of NK cells and non-NK ILCs and plasma viral load suggest a possible connection between viremia and the activity of these cell types during the course of disease.Implications of all the available evidenceOur research shows that all circulating ILCs, including non-NK ILCs, are activated, proliferating, and correlate with viral load in acute HFRS patients, indicating a general involvement in human hantavirus infection and disease. Being the first comprehensive study on ILCs in hantavirus infections, further research will give relevant insight into the roles of ILCs in disease pathogenesis and protection.

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Generation of plasma cells and CD27⁻IgD⁻ B cells during hantavirus infection is associated with distinct pathological findings

Abstract: B-cell responses during hantavirus infectionPF Kerkman et al.

Cited by 7 publications

References 59 publications

Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

Alternative B Cell Differentiation During Infection and Inflammation

Innate lymphoid cells are activated and their levels correlate with viral load in patients with Puumala hantavirus caused hemorrhagic fever with renal syndrome

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Generation of plasma cells and CD27−IgD− B cells during hantavirus infection is associated with distinct pathological findings

Abstract: B-cell responses during hantavirus infectionPF Kerkman et al.

Cited by 7 publications

References 59 publications

Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption

Alternative B Cell Differentiation During Infection and Inflammation

Innate lymphoid cells are activated and their levels correlate with viral load in patients with Puumala hantavirus caused hemorrhagic fever with renal syndrome

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Generation of plasma cells and CD27⁻IgD⁻ B cells during hantavirus infection is associated with distinct pathological findings