[Show abstract][Hide abstract] ABSTRACT: Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity.
[Show abstract][Hide abstract] ABSTRACT: We describe a family with the rare mutation R11X that leads to a truncated CD40 ligand (CD40L) missing the intracellular domain. The index case had detectable CD40L expression and presented at the age of 41 years with cerebral toxoplasmosis. A brother and two nephews were also identified as having the same mutation but exhibited milder and variable phenotypes. The older affected nephew had a moderately depressed immunoglobulin G level and a history of pneumonia at 4 months of age. The younger nephew suffered from sinusitis with normal immunoglobulin levels. Both nephews had absent antibody responses to a protein antigen with conserved responses to polysaccharide antigens. The two sisters of the index case are carriers who had elevated levels of IgM but remain well. This mutation may affect CD40 ligand function by reducing cell surface levels, diminishing CD40 interaction or disrupting CD40L intracellular signalling in T cells. The variable phenotype in members of this family offers an opportunity to further understand the CD40-CD40L signalling pathway in human immune responses.
No preview · Article · Feb 2012 · Journal of Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: Common variable immune deficiency (CVID) is the commonest symptomatic primary immunodeficiency and represents a heterogenous collection of disorders resulting mostly in antibody deficiency and recurrent infections. However, autoimmunity, granulomatous inflammation and malignancy frequently occur as part of the syndrome. The etiology of the condition has been poorly understood although in recent years, significant progress has been made in elucidating genetic mechanisms that can result in a CVID phenotype. In parallel to this, advances in treatment of the condition have also resulted in improved survival and quality of life for patients. There still remains significant work to be done in improving our understanding of the disease. In addition, recognition of the condition remains poor with significant diagnostic delays and avoidable morbidity. In this article, we review CVID with a particular focus on the areas of improving diagnosis and classification, recent developments in understanding the underlying etiology and genetics; and current treatment and monitoring recommendations for patients.
No preview · Article · Jan 2011 · Advances in Immunology
[Show abstract][Hide abstract] ABSTRACT: A history of anaphylaxis after transfusion of immunoglobulin A (IgA)-containing blood products in selective IgA-deficient (sIgAD) patients can be a major problem, particularly in emergencies, when large quantities of blood products are required.
A 19-year-old woman with end-stage Type 2 autoimmune hepatitis required liver transplantation as her only remaining treatment option. However, she also had sIgAD, anti-IgA antibodies, and episodes of anaphylaxis after receiving IgA-containing blood products. Liver transplantation would have been extremely challenging due to the difficulty of obtaining sufficient blood products from suitable IgA-deficient donors. Hence, it became imperative to devise a protocol to desensitize her to IgA-containing blood products.
Using a continuous infusion of an IgA-enriched (6 mg/mL IgA) immunoglobulin preparation with gradual increases in concentration, she was successfully desensitized to IgA. Consequently, she was able to receive standard platelets, fresh-frozen plasma, and red blood cells with no complications.
This approach could prove very useful in similar cases that may require administration of large quantities of blood products particularly in emergency lifesaving circumstances.
[Show abstract][Hide abstract] ABSTRACT: The identification of mutations in the inducible costimulator (ICOS) gene in nine patients with common variable immunodeficiency (CVID) was a major breakthrough. CVID is a complex, highly heterogeneous primary immunodeficiency disease, and the discovery of these mutations revealed a molecular basis. ICOS belongs to the CD28 family of costimulatory molecules and is expressed exclusively on activated T cells. It has at least three critical functions: germinal center formation, isotype class switching, and the development of memory B cells. The discovery of human ICOS deficiency showed that a monogenic disorder could account for the full spectrum of manifestations seen in childhood and adulthood-onset CVID, including autoimmune, inflammatory, and malignant disease complications, as well as recurrent infections. Moreover, this discovery showed that a disorder which had previously been perceived as a B-cell disease might in fact have its genetic origin in human T cells. In this article, we review the role of ICOS in the mammalian immune system and human disease, as well as the discovery and characteristics of patients with ICOS deficiency. Finally, we also discuss how these 'human knockouts' have contributed to our understanding of ICOS functions and have suggested potential avenues for using therapeutic ICOS manipulation to treat other diseases.
No preview · Article · Jun 2009 · Immunological Reviews
[Show abstract][Hide abstract] ABSTRACT: This article reviews the primary immunodeficiencies that result in hypogammaglobulinemia or predominantly antibody deficiency disorders. This group makes up the largest proportion of patients with primary immunodeficiency. Significant advances have been made in understanding the molecular basis and clinical characteristics of patients with the more severe forms of antibody deficiency in the last 6 years. Recognition of these disorders remains poor with significant diagnostic delay. The milder forms of antibody deficiency disorders, especially those with normal total serum immunoglobulin G levels, remain poorly characterized and understood. Further work remains to be done in understanding and recognizing these syndromes to benefit patient care and foster further knowledge of the immune system.
No preview · Article · Dec 2008 · Immunology and Allergy Clinics of North America
[Show abstract][Hide abstract] ABSTRACT: Cerebral toxoplasmosis can occur outside the setting of advanced HIV immunodeficiency or drug-induced immunosuppression. A case of cerebral toxoplasmosis is reported in a previously healthy 41-year-old man who was found to have a genetic defect in CD40 ligand, resulting in the X linked hyper-IgM syndrome despite normal surface protein expression on flow cytometry. This highlights the fact that primary immunodeficiencies can first present late in life with a relatively mild phenotype and should be considered in the differential diagnosis of opportunistic infections in non-HIV infected patients; in addition, normal protein expression does not necessarily rule out hypomorphic mutations.
No preview · Article · Dec 2008 · Journal of clinical pathology
[Show abstract][Hide abstract] ABSTRACT: Systemic lupus erythematosus (SLE) is typically associated with hypergammaglobulinaemia but has been described in the setting of hypogammaglobulinaemia as well. The purpose of this article is to describe various cases of SLE and hypogammaglobulinaemia, review the literature and present management strategies for hypogammaglobulinaemia in SLE.
We describe five patients with SLE and antibody deficiency, and review the literature exploring the relationship between the two.
Various types of antibody deficiency syndromes, including common variable immunodeficiency (CVID), IgA deficiency, IgM deficiency, drug-induced hypogammaglobulinaemia and hypogammaglobulinaemia secondary to nephrotic syndrome can occur in SLE. Antibody deficiency states can be treated with antibiotics and replacement immunoglobulin therapy (particularly CVID) but sometimes close monitoring is all that is required.
Measurement of immunoglobulin levels is useful in SLE to identify coexisting antibody deficiency and the later development of hypogammaglobulinaemia. This allows monitoring and appropriate treatment to be instituted.
Full-text · Article · Aug 2008 · Rheumatology (Oxford, England)
[Show abstract][Hide abstract] ABSTRACT: Common variable immunodeficiency (CVID) represents a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infection and by inflammatory, granulomatous, and autoimmune complications. Recently, there have been significant advances in understanding the pathogenesis of the disease, with five genetic mutations identified in patients who have a CVID phenotype. Clinical care also has progressed with refinements in treatment and the development of classification schemes for prognostic and research purposes. Significant delays in diagnosis remain, however. It is likely that more genetic defects will be identified in the future, further shrinking the pool of patients who have CVID of unknown cause.
No preview · Article · Jun 2008 · Immunology and Allergy Clinics of North America
[Show abstract][Hide abstract] ABSTRACT: Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play critical roles in B cell development and antibody production. Primary antibody deficiencies in humans might therefore reflect a deficit in MDCs and/or PDCs. We tested this hypothesis by measuring dendritic cell (DC) subset numbers in patients with common variable immunodeficiency (CVID), X-linked agammaglobulinaemia (XLA) and specific polysaccharide antibody deficiency (SPAD). In CVID both MDC and PDC numbers were markedly reduced. There was a graded reduction in all DC subsets across the Freiburg CVID groups (memory B cell classification) and the greatest deficit was seen in group Ia cases with the most severe disease. In contrast, MDC numbers alone were reduced in XLA whilst in SPAD the DC numbers were normal. In CVID, the number of MDCs correlated strongly with switched memory B cell percentage and total B cell count. Low numbers of DCs correlated with a greater incidence of autoimmunity, splenomegaly and granulomatous disease, and a higher incidence of clinical complications. Measurement of MDC and PDC numbers provides both prognostic information for clinical management and classification of CVID cases for future pathogenetic research. Our findings are consistent with the hypothesis that deficits in DC subsets are a critical feature in CVID.
No preview · Article · May 2008 · Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: Collagenous colitis is a poorly understood condition, associated with autoimmunity, which results in watery, nonbloody diarrhea . Common variable immunodefi ciency (CVID) is a heterogeneous group of antibody defi ciency disorders resulting in recurrent infection, autoimmunity, malignancy, and inflammatory complications . CVID is diagnosed when there is marked reduction in both immunoglobulin (Ig) G and at least 1 other immunoglobulin isotype and a failure to respond to vaccination after exclusion of other causes of hypogammaglobulinemia . Gastrointestinal manifestations are common although there has been just 1 report of an atypical presentation of collagenous colitis in CVID . We describe a second case of a patient with CVID and typical features of collagenous colitis, in whom fecal calprotectin was used as an infl ammatory marker. The condition was treated successfully with budesonide. A 25-year-old woman was diagnosed with CVID in 2000 and commenced on intravenous immunoglobulin therapy after presenting with recurrent sinopulmonary infections since childhood. She had a history of intermittent nonbloody diarrhea from the 1990s, with a weight loss of 5 to 10 kg in 1996. Several nondiagnostic colonoscopies were performed during that time, but it was not until 2001 that collagenous colitis was found. The patient declined steroid treatment and received cholestyramine instead. The diarrhea improved but in late 2004, the patient developed a fl are-up, with motions occurring 8 to 12 times a day. This was associated with a weight loss of 5 kg over 3 months. Stool samples were negative for common pathogens, including Giardia. The patient was treated empirically with metronidazole, which made no difference. Inflammatory markers (C-reactive protein and erythrocyte sedimentation Figure. Collagenous colitis. A tihickened subepithelial eosinophilic plate consistent with collagen deposition confi rmed by Verhoeff-van Gieson staining for collagen.
No preview · Article · Feb 2008 · Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología
[Show abstract][Hide abstract] ABSTRACT: Belimumab (LymphoStat-B (R)) is a fully human monoclonal antibody directed against soluble BAFF (B-cell-activating factor), which plays a role in B-cell maturation and survival, as well immunoglobulin (Ig) class switching. Its use is being investigated in autoantibody-mediated diseases and available data show that it is effective for reducing the signs and symptoms of systemic lupus erythematosus (SLE) in anti-dsDNA-seropositive patients. Both preclinical and phase I clinical studies showed that belimumab depleted B-cells and was safe and well tolerated. A phase 11 clinical study in rheumatoid arthritis demonstrated a relatively modest clinical benefit, and a phase II clinical study in SLE did not meet primary efficacy endpoints. Both phase II studies showed good safety and tolerability. Two phase III clinical trials in SLE are now open for recruitment.
No preview · Article · Aug 2007 · Drugs of the Future
[Show abstract][Hide abstract] ABSTRACT: Anaphylaxis, acute coronary syndrome and pulmonary embolism are conditions commonly seen in the acute medical setting which can be difficult to diagnose. Delay in establishing the correct diagnosis can result in either delayed or inappropriate treatment, and subsequent morbidity and mortality. The cases we present highlight the necessity of good clinical assessment when evaluating such patients.
No preview · Article · Mar 2007 · Southern Medical Journal