Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency

Fraz, Mai Sasaki Aanensen; Michelsen, Annika; Moe, Natasha; Aaløkken, Trond Mogens; Macpherson, Magnhild Eide; Nordøy, Ingvild; Aukrust, Pål; Taraldsrud, Eli; Holm, Are Martin; Ueland, Thor; Jørgensen, Silje Fjellgård; Fevang, Børre

doi:10.1007/s10875-022-01318-1

Cited by 14 publications

(11 citation statements)

References 48 publications

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“…Thirty-one case reports and case series reported the use of CT in the diagnostic work up ( 12 – 22 , 26 – 45 ). Thirteen observational studies relied primarily on CT as their only criteria for CVID-ILD ( 2 , 23 , 27 , 46 – 55 ), while 13 studies required either histological confirmation ( 5 , 24 , 25 , 56 – 63 ) or an impairment in pulmonary function ( 64 , 65 ) in addition to the detection of relevant CT abnormalities. As CT imaging was the basis for the diagnosis of CVID-ILD, CT imaging was abnormal in all patients.…”

Section: Resultsmentioning

confidence: 99%

“…Common variable immunodeficiency disorders (CVID) are the most prevalent primary symptomatic immunodeficiencies (PID), characterised by hypogammaglobulinemia and impaired immune responses to infections and vaccinations ( 1 , 2 ). The two major clinical manifestations of CVID are recurrent, mainly bacterial infections and complications secondary to dysregulation of the immune system.…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review

et al. 2023

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IntroductionCommon variable immunodeficiency related interstitial lung disease (CVID-ILD, also referred to as GLILD) is generally considered a manifestation of systemic immune dysregulation occurring in up to 20% of people with CVID. There is a lack of evidence-based guidelines for the diagnosis and management of CVID-ILD.AimTo systematically review use of diagnostic tests for assessing patients with CVID for possible ILD, and to evaluate their utility and risks.MethodsEMBASE, MEDLINE, PubMed and Cochrane databases were searched. Papers reporting information on the diagnosis of ILD in patients with CVID were included.Results58 studies were included. Radiology was the investigation modality most commonly used. HRCT was the most reported test, as abnormal radiology often first raised suspicion of CVID-ILD. Lung biopsy was used in 42 (72%) of studies, and surgical lung biopsy had more conclusive results compared to trans-bronchial biopsy (TBB). Analysis of broncho-alveolar lavage was reported in 24 (41%) studies, primarily to exclude infection. Pulmonary function tests, most commonly gas transfer, were widely used. However, results varied from normal to severely impaired, typically with a restrictive pattern and reduced gas transfer.ConclusionConsensus diagnostic criteria are urgently required to support accurate assessment and monitoring in CVID-ILD. ESID and the ERS e-GLILDnet CRC have initiated a diagnostic and management guideline through international collaboration.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022276337.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review

et al. 2023

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“…Summarizing literature related to COVID-19 and other infections and vaccines, we find that most CVID patients have preserved clinical or in vitro cellular immunity with significant impairment in some patients ( Figure 2 ). The definition of CVID and inclusion/exclusion of patients with T cell lymphopenia is of importance but notably, there is T-cell dysregulation also in CVID-patients with CD4 >200 x 10 9 /l ( 12 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…A monogenic cause of disease is found in 10-20% of patients ( 11 ). CVID patients are also characterized by an inverted CD4/8 T-cell ratio, a relative CD4+ T-cell lymphopenia and markers of T-cell activation and exhaustion, pointing to an underlying T-cell dysregulation ( 12 – 16 ). The impact of T-cell dysregulation on cellular immunity in CVID is not clear, and we will here summarize available literature on cellular immunity in CVID with a particular focus on COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Cellular immunity in COVID-19 and other infections in Common variable immunodeficiency

Løken

Fevang

2023

Front. Immunol.

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COVID-19 has shed light on the role of cellular immunity in the absence of humoral response in different patient groups. Common variable immunodeficiency (CVID) is characterized by impaired humoral immunity but also an underlying T-cell dysregulation. The impact of T-cell dysregulation on cellular immunity in CVID is not clear, and this review summarizes available literature on cellular immunity in CVID with a particular focus on COVID-19. Overall mortality of COVID-19 in CVID is difficult to assess, but seems not significantly elevated, and risk factors for severe disease mirrors that of the general population, including lymphopenia. Most CVID patients have a significant T-cell response to COVID-19 disease with possible cross-reactivity to endemic coronaviruses. Several studies find a significant but impaired cellular response to basal COVID-19 mRNA vaccination that is independent of an antibody response. CVID patients with infection only have better cellular responses to vaccine in one study, but there is no clear association to T-cell dysregulation. Cellular response wane over time but responds to a third booster dose of vaccine. Opportunistic infection as a sign of impaired cellular immunity in CVID is rare but is related to the definition of the disease. CVID patients have a cellular response to influenza vaccine that in most studies is comparable to healthy controls, and annual vaccination against seasonal influenza should be recommended. More research is required to clarify the effect of vaccines in CVID with the most immediate issue being when to booster the COVID-19 vaccine.

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“…In a recent study by Fraz et al, GLILD patients' sera, compared to CVID patients with other non-infectious complications, were found to have higher levels of soluble CD25 and T-cell immunoglobulin and mucin domain-3. Combined with the Th1 response signature cytokines TNF and IFN-γ, these findings suggest that activated T cells play an important role in GLILD pathogenesis 29 .…”

Section: Introductionmentioning

confidence: 92%

Dysregulated lymphocyte antigen receptor signaling in common variable immunodeficiency with granulomatous lymphocytic interstitial lung disease

Lui¹,

Ghosh²,

Rymaszewski³

et al. 2023

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Purpose A subset of common variable immunodeficiency (CVID) patients either present with or develop autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling pathways in CVID and CVID with GLILD (CVID/GLILD) remain undefined, which hinders the discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches. Methods To identify perturbations of immune cell subsets and TCR/BCR downstream signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients. Results Patients with CVID, regardless of GLILD status, had increased frequency of HLADR+ CD4+ T cells, CD57+ CD8+ T cells, and CD21lo B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21lo B cells showed perturbed BCR-mediated protein kinase B and extracellular signal-regulated kinase activation, while HLADR+ CD4+ T cells and CD57+ CD8+ T cells displayed disrupted TCR-mediated activation of kinases most proximal to the antigen receptor. Conclusion Lymphocyte populations from CVID/GLILD patients exhibit an activated phenotype and discordant antigen receptor signaling. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.

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Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency

Cited by 14 publications

References 48 publications

Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review

Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review

Cellular immunity in COVID-19 and other infections in Common variable immunodeficiency

Dysregulated lymphocyte antigen receptor signaling in common variable immunodeficiency with granulomatous lymphocytic interstitial lung disease

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