Primary antibody deficiency (PAD) is a heterogenous group of primary immunodeficiencies characterized by absent or impaired B-cell maturation and/or antibody production. Common variable immunodeficiency (CVID), X-linked Agammablobulinemia (XLA) and Autosomal Recessive Agammaglobulinemia (ARA) are the main forms included in this group. X-Linked Agammaglobulinaemia (XLA), caused by defects in the Bruton Tyrosine Kinase (Btk) gene, accounts for 85% of cases of primary agammaglobulinaemia and results in the failure of B-lymphocyte maturation with absent or very low serum immunoglobulin levels. Although the major part of agammaglobulinemic patients are males (as BTK is X-linked), 5–7% of cases are caused by mutations in components of the pre-B cell receptor and also affect female patients. This group of disorders has autosomal recessive inheritance (ARA). Common variable immunodeficiency (CVID) is the most frequent symptomatic antibody deficiency diagnosed in adulthood. CVID represents an “umbrella diagnosis” rather than a single diagnostic entity, gathering a wide range of primary humoral defects characterized by reduced serum levels of IgG, IgA, and/or IgM, with impaired antibody production in response to pathogens.
The mainstay of therapy of PAD is immunoglobulin replacement therapy (IgRT) that has proven, over the past four decades, to reduce significantly the burden of infections and improve the outcome of PAD patients. However, IgRT appears to be not effective in the prevention or treatment of the non-infectious complications that occur in a large part of subjects and have progressively become the major cause of mortality, especially in CVID. These complications include autoimmunity, interstitial lung disease, granulomatous disease, gastrointestinal inflammatory disease, lymphoid hyperplasia, liver disease, cancer and lymphoma and may lead, in the case of CVID, to an 11-fold increase of morbidity and mortality compared to “infections-only” patients. Of note, multiple autoimmune and inflammatory complications often occur in the same patient, thus suggesting an interlinked pathogenesis with the hallmark of immune dysregulation. Therefore, a better understanding of the immune dysregulation associated with these non-infectious complications is required in order to improve therapeutic options for these subjects. Despite the identification of both new monogenic defects linked to the B cell dysfunction and a number of immunological impairments associated with the clinical phenotype, the pathogenesis of non-infectious manifestations of PAD remains poorly understood.
Therefore, the main goal of this Research Topic is to shed light on the clinical and immunological characterization, the pathogenesis and the treatment advances of non-infectious complications of PAD. We welcome the submission of Original Research articles, Commentary, Opinion and Reviews covering the following themes:
- Molecular defects associated with non-infectious complications of PAD.
- Cellular characterization of peripheral blood and tissue inflammatory infiltrates in non-infectious complications of PAD.
- Clinical phenotypes and correlation with immunological defects of non-infectious complications of PAD.
- Safety and effectiveness of the current treatment options of non-infectious complications of PAD.
- New therapeutic regimens for non-infectious complications of PAD.
Primary antibody deficiency (PAD) is a heterogenous group of primary immunodeficiencies characterized by absent or impaired B-cell maturation and/or antibody production. Common variable immunodeficiency (CVID), X-linked Agammablobulinemia (XLA) and Autosomal Recessive Agammaglobulinemia (ARA) are the main forms included in this group. X-Linked Agammaglobulinaemia (XLA), caused by defects in the Bruton Tyrosine Kinase (Btk) gene, accounts for 85% of cases of primary agammaglobulinaemia and results in the failure of B-lymphocyte maturation with absent or very low serum immunoglobulin levels. Although the major part of agammaglobulinemic patients are males (as BTK is X-linked), 5–7% of cases are caused by mutations in components of the pre-B cell receptor and also affect female patients. This group of disorders has autosomal recessive inheritance (ARA). Common variable immunodeficiency (CVID) is the most frequent symptomatic antibody deficiency diagnosed in adulthood. CVID represents an “umbrella diagnosis” rather than a single diagnostic entity, gathering a wide range of primary humoral defects characterized by reduced serum levels of IgG, IgA, and/or IgM, with impaired antibody production in response to pathogens.
The mainstay of therapy of PAD is immunoglobulin replacement therapy (IgRT) that has proven, over the past four decades, to reduce significantly the burden of infections and improve the outcome of PAD patients. However, IgRT appears to be not effective in the prevention or treatment of the non-infectious complications that occur in a large part of subjects and have progressively become the major cause of mortality, especially in CVID. These complications include autoimmunity, interstitial lung disease, granulomatous disease, gastrointestinal inflammatory disease, lymphoid hyperplasia, liver disease, cancer and lymphoma and may lead, in the case of CVID, to an 11-fold increase of morbidity and mortality compared to “infections-only” patients. Of note, multiple autoimmune and inflammatory complications often occur in the same patient, thus suggesting an interlinked pathogenesis with the hallmark of immune dysregulation. Therefore, a better understanding of the immune dysregulation associated with these non-infectious complications is required in order to improve therapeutic options for these subjects. Despite the identification of both new monogenic defects linked to the B cell dysfunction and a number of immunological impairments associated with the clinical phenotype, the pathogenesis of non-infectious manifestations of PAD remains poorly understood.
Therefore, the main goal of this Research Topic is to shed light on the clinical and immunological characterization, the pathogenesis and the treatment advances of non-infectious complications of PAD. We welcome the submission of Original Research articles, Commentary, Opinion and Reviews covering the following themes:
- Molecular defects associated with non-infectious complications of PAD.
- Cellular characterization of peripheral blood and tissue inflammatory infiltrates in non-infectious complications of PAD.
- Clinical phenotypes and correlation with immunological defects of non-infectious complications of PAD.
- Safety and effectiveness of the current treatment options of non-infectious complications of PAD.
- New therapeutic regimens for non-infectious complications of PAD.
