Hypogammaglobulinemia and immune dysregulation—not just 2 sides of a coin

Hypogammaglobulinemia and immune dysregulation, defined by clinical manifestations of an autoreactive adaptive immune system, often coexist. This is most prominently observed in complex forms of common variable immunodeficiency (CVID) and frequently recognized within the pathologic spectrum of monogenic defects leading to inborn errors of immunity (IEIs),1Grimbacher B. Warnatz K. Yong P.F. Korganow A.S. Peter H.H. The crossroads of autoimmunity and immunodeficiency: lessons from polygenic traits and monogenic defects.J Allergy Clin Immunol. 2016; 137: 3-17Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar which raises the question of a causal relationship between both phenomena. Hypogammaglobulinemia and immune dysregulation are not mutually inclusive, as demonstrated by the lack of immune dysregulation in most patients with agammaglobulinemia and many patients with CVID on the one hand and patients recognized as having IEIs and immune dysregulation without hypogammaglobulinemia on the other hand. Rather, it seems that hypogammaglobulinemia and immune dysregulation are 2 sides of a coin with shared genetic and/or dysfunctional origin, in that impaired B-cell differentiation and selection contribute to the development of both hypogammaglobulinemia and autoimmunity. Yet, there are some observations that support a potential causal relationship between both phenomena (Fig 1). For example, the therapeutic use of high-dose immunoglobulins for their immune regulatory capacity seems to suggest that immunoglobulins can play a potential role in prevention of immune dysregulation. Additionally, selective IgA deficiency or IgA deficiency in the context of other IEIs potentially contribute to the emergence of an altered adaptive immune system and risk of immune dysregulation via its association with dysbiosis and a disturbed mucosal barrier function. Yet, only a limited number of these patients develop immune dysregulation, and it has been suggested that IgA deficiency and immune dysregulation might be a common outcome of an HLA-associated multigenic background.2Wang N. Shen N. Vyse T.J. Anand V. Gunnarson I. Sturfelt G. et al.Selective IgA deficiency in autoimmune diseases.Mol Med. 2011; 17: 1383-1396Crossref PubMed Scopus (155) Google Scholar On the other hand, immune dysregulation might cause hypogammaglobulinemia by affecting core sites of B-cell differentiation, possibly during early B-cell ontogeny but also at the sites of peripheral memory formation (ie, secondary lymphoid tissues) by altering germinal center (GC) structure or function and/or their long-term homing sites in plasma cell niches within the bone marrow (BM). The most recent evidence for this is seen in the altered humoral immune system in patients with active hemophagocytic lymphohistiocytosis. In this disease, a TH1 cell–driven immune dysregulation is associated with an altered B-cell development in the BM and a severely disturbed GC formation, both of which recover after successful treatment of the immune dysregulation.3Shim J, Park S, Venkateswaran S, Kumar D, Prince C, Parihar VC, et al. Early B cell development and B cell maturation are impaired in patients with active hemophagocytic lymphohistiocytosis [e-pub ahead of print]. Blood https://doi.org/10.1182/blood.2023020426. Accessed September 27, 2023.Google Scholar A similar causal relationship might be underlying the observations that in about 10% of patients with CVID, the onset of autoimmune cytopenia predates the manifestation of humoral immunodeficiency, which coincides with nodular infiltration of BM by CD8 and CD4 T cells and altered GC structures in lymph nodes. Also in these patients, a TH1 cell–driven inflammatory environment has been linked to dysregulation of the 2 hubs of humoral immunity.4Unger S. Seidl M. van Schouwenburg P. Rakhmanov M. Bulashevska A. Frede N. et al.TH1 phenotype of T follicular helper cells indicates an IFNgamma-associated immune dysregulation in CD21low CVID patients.J Allergy Clin Immunol. 2018; 141: 730-740Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Whether this is mainly an effect on the lymphocyte or stromal environment in both niches remains to be seen. Potential evidence from monogenic disorders for hypogammaglobulinemia evolving secondary to immune dysregulation derives from the rapidly evolving group of IEIs with genetic defects affecting regulatory T (Treg) cell development or function (Tregopathies).5Bacchetta R. Weinberg K. Thymic origins of autoimmunity-lessons from inborn errors of immunity.Semin Immunopathol. 2021; 43: 65-83Crossref Scopus (5) Google Scholar These defects encompass hypogammaglobulinemia and autoimmune disorders expanding from cytopenias, colitis, and immune endocrinopathies to lymphocytic infiltration of target organs and predisposition to lymphoid malignancies. Cytotoxic T-lymphocyte antigen-4 (CTLA-4), which is a critical checkpoint receptor, controls T-cell activation by regulating T-cell costimulation. Patients with monoallelic CTLA4 mutations express reduced levels of CTLA-4 on their Treg cells. This is associated with inadequately controlled follicular helper T cell and autoreactive B-cell responses within dysregulated GC reactions, resulting in hypogammaglobulinemia.6Gámez-Díaz L. Seidel M.G. Different apples, same tree: visualizing current biological and clinical insights into CTLA-4 insufficiency and LRBA and DEF6 deficiencies.Front Pediatr. 2021; 9662645Crossref Scopus (11) Google Scholar A direct effect of CTLA-4 insufficiency on early B-cell maturation and the loss of B-cell central tolerance remains elusive. Interestingly, the use of mAbs blocking CTLA-4 for immune checkpoint inhibition in cancer treatment, a drug-induced phenocopy of CTLA-4 insufficiency, frequently triggers immune dysregulation but not hypogammaglobulinemia, suggesting an additional level of immune disruption in genetic CTLA-4 insufficiency. Among other Tregopathies, LPS-responsive beige-like anchor protein (LRBA) and differentially expressed in FDCP 6 homolog (DEF6) deficiencies (where biallelic mutations in either LRBA or DEF6 enhance lysosomal degradation and impair surface trafficking of CTLA-4) cause immune dysregulation with hypogammaglobulinemia.6Gámez-Díaz L. Seidel M.G. Different apples, same tree: visualizing current biological and clinical insights into CTLA-4 insufficiency and LRBA and DEF6 deficiencies.Front Pediatr. 2021; 9662645Crossref Scopus (11) Google Scholar In contrast, 2 other classical Tregopathies, IPEX and CD25 deficiency, are rather rarely associated with hypogammaglobulinemia, suggesting a special role of CTLA-4 in this causal relationship of immune dysregulation and hypogammaglobulinemia. Also, the only described patient with PD-1 deficiency, affecting the other immune checkpoint, experienced mycobacterial infection and autoimmunity but did not develop hypogammaglobulinemia during the first 10 years of life.7Ogishi M. Yang R. Aytekin C. Langlais D. Bourgey M. Khan T. et al.Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.Nat Med. 2021; 27: 1646-1654Crossref PubMed Scopus (16) Google Scholar Additional patients will be needed to confirm the absence of hypogammaglobulinemia in these autoimmune-prone patients. The special role of the cytokine milieu in this pas de deux is supported by its high prevalence in patients with monogenic STAT3 gain of function (GOF), STAT1 GOF mutations, and SOCS1 deficiency,8Toth K.A. Schmitt E.G. Cooper M.A. Deficiencies and dysregulation of STAT pathways that drive inborn errors of immunity: lessons from patients and mouse models of disease.J Immunol. 2023; 210: 1463-1472Crossref Scopus (0) Google Scholar affecting IL-21 and interferon signaling among many other things. Unraveling the exact combination of altered cytokine signaling and activation of secondary pathways affecting the decisive sites of humoral immunity causing both autoimmunity and hypogammaglobulinemia will provide further insights into the shared pathogenesis of both manifestations. Yet, hypogammaglobulinemia does not seem to be secondary to altered type I interferon signaling, as high level of type I interferon in the context of interferonopathies is rarely associated with hypogammaglobulinemia. ADA2 deficiency is the only interferonopathy with this association, and it suggests the existence of additional mechanisms behind hypogammaglobulinemia in this disorder.9Tangye S.G. Al-Herz W. Bousfiha A. Cunningham-Rundles C. Franco J.L. Holland S.M. et al.Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2022; 42: 1473-1507Crossref PubMed Scopus (268) Google Scholar Similarly, not all disorders presenting with lymphoproliferative and autoimmune disease present with hypogammaglobulinemia. Thus, autoimmune lymphoproliferative syndrome caused by the failure of FAS-induced apoptosis usually lacks hypogammaglobulinemia in the setting of extensive immune dysregulation and lymphoproliferation.9Tangye S.G. Al-Herz W. Bousfiha A. Cunningham-Rundles C. Franco J.L. Holland S.M. et al.Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2022; 42: 1473-1507Crossref PubMed Scopus (268) Google Scholar On the other hand, GOF mutations in PIK3CD and loss-of-function mutations in PIK3R1 of phosphatidylinositide 3-kinase (PI3K) lead to activation of PIK3δ and cause activated PI3-kinase delta syndrome (APDS), a human immunodysregulatory disorder with altered B-cell receptor and T-cell receptor signaling. B-cell–intrinsic defects cause defective B-cell maturation in the BM. Additionally, T-cell–intrinsic defects lead to an expansion and dysregulation of circulating and GC follicular helper T cells as well as impaired Treg cell differentiation. These factors contribute to hyperplasia of disorganized GCs, impaired class-switched B-cell memory, hypogammaglobulinemia, and autoimmunity.10Preite S. Gomez-Rodriguez J. Cannons J.L. Schwartzberg P.L. T and B-cell signaling in activated PI3K delta syndrome: from immunodeficiency to autoimmunity.Immunol Rev. 2019; 291: 154-173Crossref PubMed Scopus (47) Google Scholar Hypogammaglobulinemia, often with a hyper-IgM phenotype, autoimmunity, lymphoproliferation, B-cell lymphomagenesis, and inability to control Epstein-Barr virus (EBV) viremia represent common features of APDS. Interestingly, nearly all IEIs with susceptibility to EBV and lymphoproliferative conditions (see Table 4.7 in Tangye et al9Tangye S.G. Al-Herz W. Bousfiha A. Cunningham-Rundles C. Franco J.L. Holland S.M. et al.Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2022; 42: 1473-1507Crossref PubMed Scopus (268) Google Scholar) are often associated with both autoimmunity and hypogammaglobulinemia, suggesting a potential role of EBV infection in disturbing both immune regulation and antibody production. Additional monogenic examples of the coincidence of hypogammaglobulinemia and immune dysregulation include a few combined immunodeficiencies such as linker for activation of T cells (LAT) deficiency, where the occurrence of severe autoimmunity is associated with a progressive hypogammaglobulinemia, even after an initial hypergammaglobulinemia in some of the patients. Similarly, progressive hypogammaglobulinemia has been described in lymphocyte-specific protein tyrosine kinase (LCK) and IL2-inducible T-cell kinase (ITK) deficiency.9Tangye S.G. Al-Herz W. Bousfiha A. Cunningham-Rundles C. Franco J.L. Holland S.M. et al.Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2022; 42: 1473-1507Crossref PubMed Scopus (268) Google Scholar The same was reported in patients and mice with heterozygous mutations in SYK, where SYK inhibitors could partially restore the hypogammaglobulinemia in the mouse model.9Tangye S.G. Al-Herz W. Bousfiha A. Cunningham-Rundles C. Franco J.L. Holland S.M. et al.Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2022; 42: 1473-1507Crossref PubMed Scopus (268) Google Scholar Whereas most IEIs with coinciding hypogammaglobulinemia and immune dysregulation directly involve some T-cell dysregulation, activation-induced cytidine deaminase (AID), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and probably protein kinase C delta (PRKCD) deficiency are examples of mostly B-cell–intrinsic immunodeficiencies in which both sites of the coin are probably caused by the same genetic background rather than by one succeeding the other.9Tangye S.G. Al-Herz W. Bousfiha A. Cunningham-Rundles C. Franco J.L. Holland S.M. et al.Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2022; 42: 1473-1507Crossref PubMed Scopus (268) Google Scholar There are multiple pieces of clinical and pathogenetic evidence for a relationship between immune dysregulation and hypogammaglobulinemia, yet the ultimate proof for a causal relationship between them is the correction of immune dysregulation by antibody replacement and restoration of antibody production by correction of the immune dysregulation, respectively. This evidence is still missing for most patients with IEIs and disorders. For example, we are still lacking ways to restore local IgA production in the gastrointestinal tract so as to prove its deleterious effect on immune homeostasis. Similarly, more targeted treatments of immune dysregulation are required to investigate their effect on hypogammaglobulinemia. The first evidence for targeted treatment in selected IEIs leading to improved immunoglobulin production has emerged after treatment of a small group of patients with APDS with the PI3KD inhibitor leniolisib. In this setting, targeted pharmacologic inhibition of an overactive signaling pathway helped achieve control of both immune dysregulation and hypogammaglobulinemia in some patients. Yet, this has not been reported for treatment of patients with CTLA-4 or LRBA insufficiency by using soluble CTLA-4 fusion protein (abatacept). The fact that these deficiencies may not be sufficiently and fully replaced to restore humoral dysfunction may suggest additional layers of the defect in B-cell homeostasis in this IEI or, more likely, the insufficiently tailored site and time point–specific provision of this critical checkpoint receptor at the sites of humoral immune responses. In-depth studies of individual patients with informative rare monogenic IEIs will help unravel this unfavorable association of hypogammaglobulinemia and immune dysregulation. Supported by the Deutsche Forschungsgemeinschaft (DFG) (grants TRR130 [to K.W. and B.K.] and SFB 1160 IMPATH [to K.W.]) DFG DECIDE (to K.W.), the German Federal Ministry of Education and Research through a grant to the German Genetic Multi-Organ Auto-Immunity Network (grant 01GM2206A [to K.W.]), and the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to G.U.). Disclosure of potential conflict of interest: K. Warnatz has received a research grant from Bristol-Myers Squibb to investigate the role of abatacept in the treatment of patients with common variable immunodeficiency. The rest of the authors declare that they have no relevant conflicts of interest.