Non-Infectious Complications of Primary Antibody Deficiency

Editorial

21 April 2021

Editorial: The Complexity of Primary Antibody Deficiencies

Isabella Quinti

Giuseppe Spadaro

Stephen Jolles

and

Antonio Condino-Neto

2,745 views

2 citations

Editors

Giuseppe Spadaro

Department of Translational Medical Sciences, School of Medicine and Surgery, University of Naples Federico II

Isabella Quinti

Sapienza University of Rome

Stephen Jolles

University Hospital of Wales

Antonio Condino-Neto

University of São Paulo

Impact

sFLC levels in the differential diagnosis of hypogammaglobulinemia. CVID patients displayed lower of κ chains serum levels (A) and lower λ chains serum levels (B) in comparison to UAD, SID and LPDs groups. CVID had also lower FLCr in comparison to LPDs (C). Individual values, median, and IQR are represented. Levels of significance for comparison with CVID group by u test: *P ≤ 0.05, ****P ≤ 0.0001.

Original Research

31 March 2020

Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype

Riccardo Scarpa

, 17 more and

Francesco Cinetto

7,194 views

8 citations

The multidisciplinary approach to the care of patients with primary antibody deficiency and bronchiectasis.

Review

31 March 2020

Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

Luke A. Wall

, 2 more and

Ricardo U. Sorensen

11,480 views

33 citations

Main causes of liver disease in CVID. The clinical spectrum of CVID includes predisposition to infections, immune-dysregulation-related manifestations (i.e., autoimmunity or lymphocytic infiltration) and malignancies. Liver involvement in CVID may rely on each of these three pathogenetic mechanisms. NRH is the most common histopathologic finding in CVID and is thought to be related, at least in part, to an auto-reactive T-cell intrasinusoidal infiltration, while a subset of patients may present a more severe portal inflammatory infiltration consistent with inferface hepatitis, as observed in autoimmune hepatitis. Splenomegaly is a common clinical feature in CVID patients and contributes to the increase of portal venous pressure, as shown in detail in Figure 2. In past decades, contaminated immunoglobulin preparations were a significant cause of iatrogenic viral hepatitis (i.e., HBV, HCV, CMV, and EBV), while Giardia lamblia, which is a common cause of chronic enteritis in CVID, may affect liver as extra-intestinal localization. Finally, liver may be target of both primary and metastatic malignancies. These latter may be the result of both gastrointestinal cancers (i.e., stomach and colon) and hematological malignancies. The figure was created with Biorender.com.

Review

28 February 2020

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

Antonio Pecoraro

, 3 more and

Giuseppe Spadaro

17,043 views

46 citations

Original Research

07 February 2020

Non-infectious Complications of Common Variable Immunodeficiency: Updated Clinical Spectrum, Sequelae, and Insights to Pathogenesis

Hsi-en Ho

and

Charlotte Cunningham-Rundles

Non-infectious complications in common variable immunodeficiency (CVID) have emerged as a major clinical challenge. Detailed clinical spectrum, organ-specific pathologies and associated sequelae from 623 CVID patients followed in New York since 1974 were analyzed, and recent insights to pathogenesis were reviewed. Non-infectious manifestations were present in 68.1% of patients, and they do not tend to be present in isolation. They include autoimmunity (33.2%), chronic lung disease (30.3%), lymphoid hyperplasia/splenomegaly (20.9%), liver disease (12.7%), granulomas (9.3%), gastrointestinal disease (7.3%), lymphoma (6.7%), and other malignancies (6.4%). In the lungs, interstitial disease and bronchiectasis were the most common findings, with lymphoma at this site being a rare (n = 6), but serious, manifestation. Bronchiectasis was not a prerequisite for the development of interstitial disease. In the liver, granulomas and nodular regenerative hyperplasia were the most common. Gastrointestinal disease may affect any segment of the intestinal tract, with lymphoid infiltrations and villous blunting being the leading histologic findings. With progression of organ-specific diseases, a wide spectrum of associated sequelae was observed. Lymphoma was more common in females (P = 0.036)—all B cell types except in one subject. Solid organ transplantations (liver, n = 5; lung, n = 4; combined lung and heart, n = 2) and hematopoietic stem cell transplantations (for B cell lymphoma, n = 1) have rarely been performed in this cohort, with mixed outcomes. Recent identification of monogenic defects, in ~10–30% of various CVID cohorts, has highlighted the molecular pathways that can affect both antibody production and broader immune regulation. In addition, cellular defects in both innate and adaptive immune systems are increasingly recognized in this syndrome.

Chronic lung disease. (A) Lung disease types by radiographs and/or pathology reports (n = 124). (B) Interstitial lung disease pathologies (n = 46). *Thirteen out of 65 subjects with ILD had concurrent bronchiectasis. ILD, interstitial lung disease; LIP, lymphoid interstitial pneumonia; BOOP, bronchiolitis obliterans organizing pneumonia.

10,931 views

160 citations

Main characteristics of circulating TFH subsets.

Mini Review

30 January 2020

Functions of Tfh Cells in Common Variable Immunodeficiency

Corentin Le Saos-Patrinos

, 3 more and

Dorothée Duluc

6,479 views

21 citations

(A) Manhattan plot of exome-wide significant results of 535,486 SNPs between monogenic and unsolved CVID patients supporting a polygenic etiology of unsolved CVID where variants with a genotyping rate <98%, ambiguitious SNPs, evidence of deviation from Hardy-Weinberg equilibrium in controls (p < 1 × 10−4), and minor allele frequency < 1 × 10−6 were removed. Only the near-independent SNPs that do not account for linkage disequilibrium and were significantly different between monogenic and unsolved patients were included for the next step. (B) Principal component analysis (PCA) and (C) correlation matrix of significant variants discriminating monogenic and non-monogenic CVID patients. (D) MR model generated for selected variants were inputed to a considering them as direct linked with exposure (antibody deficiency) and outcome (infectious diseases). (E) Polygenic score of unsolved CVID disease was increased when the testing dataset had a lower percentage of MHC risk alleles.

Original Research

24 January 2020

Histocompatibility Complex Status and Mendelian Randomization Analysis in Unsolved Antibody Deficiency

Hassan Abolhassani

, 2 more and

Lennart Hammarström

4,218 views

6 citations

$Immunoglobulin M (IgM) memory B cells differentiate into IgA+ plasma cells in response to transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and toll-like receptor 9 (TLR9) co-stimulation. Flow-cytometry analysis after 7 days in culture with anti-TACI plus IL-4 and IL-21. The loss of intracellular CMFDA tracks cell division. (A) No proliferation is observed in mature-naive and IgM memory B cells, whereas a modest expansion of transitional B cells is observed (upper panels). The IgM/CD27 staining (lower panels) shows the loss of surface IgM in 17.0% of mature-naïve and 43.6% of IgM memory B cells (bottom panels). (B) The addition of CpG induces proliferation as shown by the loss of CMFDA fluorescence, mainly in transitional and IgM memory B cells (top panels). Differentiation into IgM+ CD27+ plasma cells is observed in all B cell types. Switched plasma cells are only generated from IgM memory B cells. (C) After 7 days with anti-TACI, a small fraction of mature-naïve B cells had switched to IgA. The addition of CpG further increased survival. Upon TACI cross-linking, almost half of the IgM memory B cells switched to IgA, but when CpG was added to the culture, IgM memory B cells differentiated into IgA+ plasma cells. (D) Graphs indicate the concentration of IgM and IgA (ng/ml) detected by ELISA in culture supernatants obtained from B cells stimulated with anti-TACI, CpG, IL-4, and IL-21. IgM can be detected in the supernatants of all B cell types, but only stimulated IgM memory B cells secreted IgA. IgG production was never detectable.$

Original Research

08 January 2020

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis

Rita Carsetti

, 14 more and

Isabella Quinti

6,484 views

46 citations

Review

10 December 2019

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Jessica D. Gereige

and

Paul J. Maglione

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.

14,967 views

62 citations