Factors Beyond Lack of Antibody Govern Pulmonary Complications in Primary Antibody Deficiency

Weinberger, Tamar; Fuleihan, Ramsay; Cunningham‐Rundles, Charlotte; Maglione, Paul J.

doi:10.1007/s10875-019-00640-5

Cited by 31 publications

(31 citation statements)

References 58 publications

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“…One possible explanation for this discrepancy is that the sample size of this cohort did not provide enough power to reach significance (only 17 of 77 patients had autoimmunity). In a separate study, BAFF levels were elevated in CVID patients with active interstitial lung disease, an inflammatory pulmonary disease linked with autoimmune cytopenias (17,25). On the other hand, BAFF levels were not elevated in those with quiescent stable disease, suggesting that increases of this cytokine might be closely tied to disease activity (67) thus offering another possible explanation for the lack of association in the aforementioned cohort.…”

Section: B Cell Dysfunction In Cvid Autoimmune Diseasementioning

confidence: 99%

“…Autoimmune cytopenias are often associated with other non-infectious complications in CVID. Compared with other CVID patients, those with ILD are more likely to have had autoimmune cytopenias (6,25). Conversely, CVID patients with autoimmune cytopenias had a higher frequency of CVID-associated non-infectious complications, including granulomatous and lymphoproliferative disease, as well as organ-specific autoimmune disease, but interestingly, not systemic autoimmunity (26).…”

Section: Overview Of Autoimmune Disease In Common Variable Immunodefimentioning

confidence: 99%

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Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Gereige

Maglione

2019

Front. Immunol.

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Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency and comprises a group of disorders with similar antibody deficiency but a myriad of different etiologies, most of which remain undefined. The variable aspect of CVID refers to the approximately half of patients who develop non-infectious complications in addition to heightened susceptibility to infection. The pathogenesis of these complications is poorly understood and somewhat counterintuitive because these patients that are defined by their immune futility simultaneously have elevated propensity for autoimmune disease. There are numerous aspects of immune dysregulation associated with autoimmunity in CVID that have only begun to be studied. These findings include elevations of T helper type 1 and follicular helper T cells and B cells expressing low levels of CD21 as well as reciprocal decreases in regulatory T cells and isotype-switched memory B cells. Recently, advances in genomics have furthered our understanding of the fundamental biology underlying autoimmunity in CVID and led to precision therapeutic approaches. However, these genetic etiologies are also associated with clinical heterogeneity and incomplete penetrance, highlighting the fact that continued research efforts remain necessary to optimize treatment. Additional factors, such as commensal microbial dysbiosis, remain to be better elucidated. Thus, while recent advances in our understanding of CVID-associated autoimmunity have been exciting and substantial, these current scientific advances must now serve as building blocks for the next stages of discovery.

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Section: B Cell Dysfunction In Cvid Autoimmune Diseasementioning

confidence: 99%

Section: Overview Of Autoimmune Disease In Common Variable Immunodefimentioning

confidence: 99%

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Gereige

Maglione

2019

Front. Immunol.

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“…In patients with CVID, bronchiectasis has been known to progress in the absence of obvious infections (31). The propensity toward autoimmunity and chronic inflammation in CVID is a proposed factor (32,33). Insights which link the concepts of autoimmunity, chronic inflammation, susceptibility to lung infections, and the importance of neutrophils may suggest another clue regarding the pathogenesis of bronchiectasis (34).…”

Section: Pathophysiology: the Immune System Inflammation And The Lungmentioning

confidence: 99%

Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

2020

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Bronchiectasis, the presence of bronchial wall thickening with airway dilatation, is a particularly challenging complication of primary antibody deficiencies. While susceptibility to infections may be the primary factor leading to the development of bronchiectasis in these patients, the condition may develop in the absence of known infections. Once bronchiectasis is present, the lungs are subject to a progressive cycle involving both infectious and non-infectious factors. If bronchiectasis is not identified or not managed appropriately, the cycle proceeds unchecked and yields advanced and permanent lung damage. Severe symptoms may limit exercise tolerance, require frequent hospitalizations, profoundly impair quality of life (QOL), and lead to early death. This review article focuses on the appropriate identification and management of bronchiectasis in patients with primary antibody deficiencies. The underlying immune deficiency and the bronchiectasis need to be treated from combined immunology and pulmonary perspectives, reflected in this review by experts from both fields. An aggressive multidisciplinary approach may reduce exacerbations and slow the progression of permanent lung damage.

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“…The pathogenesis of CVID-related ILD is presumed to be unrelated to bacterial infections because it can be seen in the absence of bronchiectasis and is not significantly associated with a history of pneumonia (21). Patients with ILD have distinct clinical and immunological phenotypes in keeping with immune dysregulation, in contrast to those without ILD or those with bronchiectasis alone (6,9,14,16,21,26,27). Furthermore, there is no current histological or molecular evidence for chronic bacterial, EBV or CMV viral infections as triggers for inflammation (16,(28)(29)(30), though granulomas in other PIDs, such as those with DNA repair defects, show evidence of vaccine derived rubella virus (31).…”

Section: Interstitial Lung Disease In Common Variable Immune Deficienmentioning

confidence: 99%

“…Furthermore, there is no current histological or molecular evidence for chronic bacterial, EBV or CMV viral infections as triggers for inflammation (16,(28)(29)(30), though granulomas in other PIDs, such as those with DNA repair defects, show evidence of vaccine derived rubella virus (31). Other related complications, including splenomegaly, autoimmune cytopaenias, persistent lymphadenopathy and lymphoproliferation, but not necessarily granulomata, occur more frequently in patients with CVID-related ILD, supporting at least a role for intrinsic immune dysregulation driving these varied features (6,9,16,21,27,32,33).…”

Section: Interstitial Lung Disease In Common Variable Immune Deficienmentioning

confidence: 99%

Histology of Interstitial Lung Disease in Common Variable Immune Deficiency

et al. 2020

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Interstitial lung disease (ILD) is an important non-infectious complication in several primary immune deficiencies. In common variable immune deficiency (CVID) it is associated with complex clinical phenotypes and adverse outcomes. The histology of ILD in CVID is heterogeneous and mixed patterns are frequently observed within a single biopsy, including non-necrotising granulomatous inflammation, lymphoid interstitial pneumonitis, lymphoid hyperplasia, follicular bronchiolitis, organizing pneumonia, and interstitial fibrosis; ILD has to be differentiated from lymphoma. The term granulomatous-lymphocytic interstitial lung disease (GLILD), coined to describe the histopathological findings within the lungs of patients with CVID with or without multisystem granulomata, is somewhat controversial as pulmonary granulomata are not always present on histology and the nature of infiltrating lymphocytes is variable. In this mini review we summarize the literature on the histology of CVID-related ILD and discuss some of the factors that may contribute to the inter- and intra- patient variability in the histological patterns reported. Finally, we highlight areas for future development. In particular, there is a need for standardization of histological assessments and reporting, together with a better understanding of the immunopathogenesis of CVID-related ILD to resolve the apparent heterogeneity of ILD in this setting and guide the selection of rational targeted therapies in different patients.

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Factors Beyond Lack of Antibody Govern Pulmonary Complications in Primary Antibody Deficiency

Cited by 31 publications

References 58 publications

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

Histology of Interstitial Lung Disease in Common Variable Immune Deficiency

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