Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses

Romberg, Neil; Coz, Carole Le; Glauzy, Salomé; Schickel, Jean Nicolas; Trofa, Melissa; Nolan, Brian E.; Paessler, Michele; Xu, Mina L; Lambert, Michele P.; Lakhani, Saquib A.; Khokha, Mustafa K.; Jyonouchi, Soma; Heimall, Jennifer; Takach, Patricia; Maglione, Paul J.; Catanzaro, Jason; Hsu, Florence Ida; Sullivan, Kathleen E.; Cunningham‐Rundles, Charlotte; Meffre, Eric

doi:10.1016/j.jaci.2018.06.012

Cited by 63 publications

(88 citation statements)

References 24 publications

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“…In another study, Romberg et al showed that germinal centers in lymph nodes from CVID patients with prominent autoimmunity display irregularly shaped hyperplastic germinal centers while germinal centers were scarce and smaller in patients without this history. Hyperplasia in these cases was accompanied by increase in the numbers of circulating follicular helper T cells, decreased regulatory T‐cells and T‐reg function . This germinal center drive appeared to correlate with fewer isotype‐switched memory B cells, lower frequencies of somatic hypermutation, and curiously, increased serum endotoxin in these subjects.…”

Section: Clinical Spectrummentioning

confidence: 92%

Common variable immune deficiency: Dissection of the variable

Cunningham‐Rundles

2018

Immunological Reviews

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Summary Starting about 60 years ago, a number of reports appeared that outlined the severe clinical course of a few adult subjects with profound hypogammaglobinemia. Puzzled by the lack of family history and adult onset of symptoms in most, the name “acquired” hypogammaglobinemia was given, but later altered to the current name common variable immune deficiency (CVID). Pathology reports remarked on the loss of lymph node architecture and paucity of plasma cells in lymphoid tissues in these subjects. While characterized by reduced serum IgG and IgA and often IgM, and thus classified amongst the B cell defects, an increasing number of cellular defects in these patients have been recognized over time. In the early years, severe respiratory tract infections commonly led to a shortened life span, but the wide spread availability of immune globulin concentrates for the last 25 years has improved survival. However, chronic non-infectious inflammatory and autoimmune conditions have now emerged as challenging clinical problems; these require further immunologic understanding and additional therapeutic measures. Recent study of this phenotypic syndrome have provided an increasingly fertile ground for the identification of autosomal recessive and now more commonly, autosomal dominant gene defects which lead to the loss of B cell development in this syndrome.

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Section: Clinical Spectrummentioning

confidence: 92%

Common variable immune deficiency: Dissection of the variable

Cunningham‐Rundles

2018

Immunological Reviews

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“…Lymphocyte immunophenotyping and in vitro proliferation of T cells in response to mitogens is typically normal in CVID . One of the hallmarks of CVID‐like primary immune regulatory disorders with associated AIC is an increase in circulating T follicular helper cells (depicted in Figure ) …”

Section: Primary Immune Regulatory Disorders Spectrum: Alps‐like/ipexmentioning

confidence: 99%

“…Histologic examination of patients with CVID‐like disease with AIC often shows expanded but bizarre arrangement of germinal centers (depicted in Figure ) . Granulomatous inflammation involving the lung, lymph nodes, liver, and skin may also be present .…”

Section: Primary Immune Regulatory Disorders Spectrum: Alps‐like/ipexmentioning

confidence: 99%

“…31 One of the hallmarks of CVID-like primary immune regulatory disorders with associated AIC is an increase in circulating T follicular helper cells (depicted in Figure 3). 38 Histologic examination of patients with CVID-like disease with AIC often shows expanded but bizarre arrangement of germinal centers (depicted in Figure 4). 38 Granulomatous inflammation involving the lung, lymph nodes, liver, and skin may also be present.…”

Section: Ipex/ipex-like Disordersmentioning

confidence: 99%

“…38 Histologic examination of patients with CVID-like disease with AIC often shows expanded but bizarre arrangement of germinal centers (depicted in Figure 4). 38 Granulomatous inflammation involving the lung, lymph nodes, liver, and skin may also be present. 30 These findings may be seen in both CVID and/or CVID-like disorders; however, their presence as well as lymphocytic infiltration of other nonlymphoid organs such as gut, lung, or brain should prompt consideration of a CVID-like disorder.…”

Section: Ipex/ipex-like Disordersmentioning

confidence: 99%

See 2 more Smart Citations

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

Chandrakasan

Chandra

Saldaña

et al. 2019

Pediatric Blood & Cancer

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An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS‐like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) and IPEX‐like disorders, common variable immunodeficiency (CVID), CVID‐like, and late‐onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case‐based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.

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TACI haploinsufficiency protects against BAFF‐driven humoral autoimmunity in mice

Jacobs

Arkatkar

et al. 2021

Eur J Immunol

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Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.

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Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses

Abstract: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

Cited by 63 publications

References 24 publications

Common variable immune deficiency: Dissection of the variable

Common variable immune deficiency: Dissection of the variable

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

TACI haploinsufficiency protects against BAFF‐driven humoral autoimmunity in mice

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