Giuseppe Spadaro

LONG-TERM FOLLOW-UP AND OUTCOME OF A LARGE COHORT OF PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

The anti-IgE/anti-FcεRIα autoantibody network in allergic and autoimmune diseases

Basophil granulocytes and tissue mast cells and their mediators play a role in the pathogenesis of several immune and inflammatory disorders. Human basophils and mast cells (FcεRI+ cells) can be activated through immunological interaction with the IgE‐FcεRI network. FcεRI+ cells can be triggered by cross‐linking between the Fab portions of IgE and multivalent antigens (direct anaphylaxis). ‘Reverse type’ anaphylaxis can occur through three distinct mechanisms: antibodies against the Fcε portion of IgE (anti‐IgE), antibodies against epitopes of the α chain of FcεRI (anti‐FcεRIα) and anti‐IgG acting on IgG–IgE complexes bound to FcεRI. Anti‐IgE autoantibodies are occasionally present even in normal donors and more frequently in a variety of allergic (chronic urticaria, atopic dermatitis and bronchial asthma) and autoimmune disorders (rheumatoid arthritis, lupus erythematosus and systemic sclerosis). IgG anti‐IgE from a small percentage of patients induces the release of mediators from human FcεRI+ cells. Some of the anti‐IgE autoantibodies present in allergic patients are non‐anaphylactogenic, thus representing a possible protective mechanism preventing the association of IgE with FcεRI. Anti‐FcεRIα autoantibodies also occur in a significant percentage of patients of chronic urticaria and probably non‐allergic asthma and some autoimmune diseases. Although anti‐IgE and anti‐FcεRIα autoantibodies, present in a percentage of patients with immune disorders, are relevant to the pathogenesis of these conditions, much remains to be learnt about their immunochemistry, their prevalence and precise role in various inflammatory diseases.

Loratadine and desethoxylcarbonyl-loratadine inhibit the immunological release of mediators from human FceRI+cells

Background Loratadine, a novel histamine H1‐receptor antagonist, is effective in the treatment of patients with seasonal and perennial rhinitis and some allergic skin disorders. Histamine and other chemical mediators are synthesized and immunologically released by human peripheral blood basophils and tissue mast cells (FcɛRI+ cells).

The human heart as a shock organ in anaphylaxis.

SummaryAnaphylaxis is a potentially fatal, immediate hypersensitivity reaction. Mast cells and basophils, by elaborating vasoactive mediators and cytokines, are the main primary effector cells of anaphylaxis. Mast cells have been identified in human heart between myocardial fibers, perivascularly, in the adventitia, and in the arterial intima. Mast cells isolated from human heart tissue (HHMC) of patients undergoing cardiac transplantation express high affinity immunglobulin E (IgE) receptors (FcεRI), C3a, C5a, and kit receptors (KIT). Anti-IgE, anti-FcεRI, and immunoglobulin superallergens induce in vitro secretion of preformed mediators (histamine, tryptase, chymase, and renin) and the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HHMC. Complement is activated and anaphylatoxin forms during anaphylaxis. C5a and C3a cause the in vitro release of histamine and tryptase from HHMC. Therapeutic (general anesthetics, protamine, etc.) and diagnostic agents (radio contrast media, etc.), which can cause anaphylactoid reactions, activate HHMC in vitro. Low concentrations of histamine and cysteinyl leukotrienes given to subjects undergoing diagnostic catheterisation caused significant systemic and coronary hemodynamic effects. These data indicate that human heart mast cells and their mediators play a role in severe anaphylactic reactions.

Treatment of mastocytosis: pharmacologic basis and current concepts

Mastocytosis is a rare, heterogeneous disorder characterized by a marked increase in mast cell density in various tissues. Mast cells from different human tissues are heterogeneous. So far, there is no cure for systemic mastocytosis. Conventional therapy is based on agents that antagonize mediators released from mast cells, drugs that inhibit the release of mediators and agents that modulate mast cell proliferation. This pharmacologic approach is satisfactory in the majority of patients with indolent mastocytosis. At the beginning of the new millennium, the therapy of severe forms of aggressive mastocytosis remains a challenge for students of this intriguing disorder.

The clinical relevance of basophil releasability

area is the possibility that groups of cytokines st imulate specific pat terns of expression of receptors and that this pa t te rn is responsible for behavior of the cell and can be diagnosed by MAb. Third, the possibility of having clinically relevant antagonists is real with the development of powerful blocking M A b and, perhaps more important , of analogues of growth factors that act as antagonists by specifically binding one of the chains of the receptors for these factors (Tables V and VI). Al though each of these reagents may have significant drawbacks in clinical use (the M A b is mur ine and the antagonist must be used in excess over ligand of approximately 100 times), each points the way for the specific design of smaller molecules that may be more po ten t and more easily administered. Finally, the effect of cyclosporine on cells o ther than T lymphocytes also points the way for the inhibition of t ranscript ion of cytokine genes in non-T cells. The particularly attractive possibility is that there exist several pathways of activation only some of the activation pathways are sensitive to cyclosporine. If this were to be the case, it may be possible to target activation pathways specific for allergy.

Role of Superallergens in Allergic Disorders

A significant percentage of allergic diseases (e.g. certain cases of intrinsic asthma, chronic idiopathic urticaria, and atopic dermatitis) cannot be explained by the classical mechanisms of IgE/allergen-mediated activation of basophils and mast cells. We found that protein Fv, an endogenous protein synthesized in the human liver and increased during viral hepatitis, act as a superallergen by binding to IgE of the VH3 family and activating human basophils and mast cells. Similarly, envelope gp120 of HIV-1 and protein A of Staphylococcus aureus are viral and bacterial superallergens, respectively, because they interact with IgE VH3+. Protein L binds to the V domain of he kappa light chains of IgE. Our results demonstrate that endogenous, viral and bacterial products activate primary effector cells of allergic disorders to release proinflammatory mediators and cytokines thereby acting as immunoglobulin superantigens (superallergens).

Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency

To the editor: In the paper by Resnick et al, the authors clearly defined lymphoma, lung impairment, hepatitis, and gastrointestinal disease as the main causes of mortality in 411 subjects with common variable immunodeficiency (CVID) followed over 4 decades in New York.[1][1] This careful analysis

Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia.

Autosomal-recessive agammaglobulinemia is a rare and heterogeneous disorder, characterized by early-onset infections, profound hypogammaglobulinemia of all immunoglobulin isotypes and absence of circulating B lymphocytes. To investigate the molecular basis of the disease, 23 patients with early-onset disease and no mutations in Bruton tyrosine kinase, the gene responsible for X-linked agammaglobulinemia, were selected and analyzed by direct sequencing of candidate genes. Two novel mutations in the μ heavy chain (μHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G>A nucleotide substitution at the −1 position of an alternative splice site in IGHM; here, we demonstrate that this mutation is indeed responsible for aberrant splicing. Comparison of bone marrow cytofluorimetric profiles in two patients carrying different mutations in the IGHM gene suggests a genotype–phenotype correlation with the stage at which B-cell development is blocked. Several new single nucleotide polymorphisms (SNPs) both in the μHC and in the λ5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology.

Prospective Study on CVID Patients with Adverse Reactions to Intravenous or Subcutaneous IgG Administration

IntroductionThe multicenter prospective study provides information on adverse reactions to intravenous and subcutaneous immunoglobulin treatment in a cohort of 262 patients with common variable immunodeficiency. Severe adverse reactions are a rare but unpredictable event that might occur also in patients who tolerate substitutive intravenous or subcutaneous immunoglobulin therapy for months or years.ResultsSubcutaneous therapy has been proved to be a safe option in the 13 patients who had to stop intravenous treatment and who remained out of immunoglobulin replacement for long periods of time. However, severe reactions to subcutaneous therapy occurred at the first or after several subcutaneous immunoglobulin administrations in 2 out of 13 patients.ConclusionTherefore, patients with previous severe reactions to intravenous immunoglobulin should be considered at particularly high risk for reaction to subcutaneous administration. In these cases, switching from in-hospital administration to home self-administration should be done with extreme care.