Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

OBJECTIVES: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM. METHODS: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback. RESULTS: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements. CONCLUSIONS: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.

Specific Antibody Deficiencies.

Patients with specific antibody deficiency (SAD) have a deficient immunologic response to polysaccharide antigens. Such patients experience sinopulmonary infections with increased frequency, duration, or severity compared with the general population. SAD is definitively diagnosed by immunologic challenge with a pure polysaccharide vaccine in patients 2 years old and older who have otherwise intact immunity, using the 23-valent pneumococcal polysaccharide vaccine as the current gold standard. Specific antibody deficiencies comprise multiple immunologic phenotypes. Treatment must be tailored based on the severity of symptoms. Most patients have a good prognosis. The deficiency may resolve over time, especially in children.

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia.

Manifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19(+) B cells (165 vs 454 vs 417 × 106L) with elevated CD19(+)CD21(low) immature (16.5%, 7.7%, and 9.1%) and CD19(+)CD21(int-high)CD38(high)IgM(high) transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19(+)CD10(-)CD27(-)CD21(high) naive B cells were highly elevated in all patients with cGVHD. CD19(+)CD27(+)IgD(+) non-class-switched (4 vs 12 vs 11 × 106/L) and class-switched (7 vs 35 vs 42 × 106/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Meningioma cordoide. A propósito de un caso y revisión de la literatura / Chordoid meningioma. Report of a case and review of the literature

El término meningioma cordoide fue usado por primeravez en 1988 para describir un tumor meníngeo que afectaba aindividuos jóvenes y que se presentaba con anemia microcíticay/o disgammaglobulinemia. Presentamos un caso de estavariante poco frecuente, que corresponde a menos del 0,5% detodos los meningiomas. Corresponde a una mujer de 69 añossin otras patologías de interés. La lesión se manifestó condolores de cabeza severos. La resonancia magnética cerebralmostró una masa tumoral supratentorial dependiente demeninge. Microscópicamente se evidenció una proliferaciónneoplásica dispuesta en lóbulos constituida por células epitelioidesy fusiformes que mostraban vacuolización del citoplasmay que descansaban sobre una matriz mixoide, basófila.Las células tumorales expresaban antígeno epitelial demembrana (EMA) y no mostraban reactividad con proteínaácida glial fibrilar, proteína S-100 ni citoqueratina. La neoplasiafue diagnosticada de meningioma cordoide (grado II de laclasificación de la Organización Mundial de la Salud)

The term chordoid meningioma was first used in 1988to describe a meningeal tumor among young people associatedwith microcytic anemia and/or dysgammaglobulinemia.We present a case of this rare variant, which comprisesless than 0.5% of all meningiomas. A 69-yr-old femalecomplained of severe headache with unremarkable physicalexamination. Brain magnetic resonance revealed a supratentorialtumoral mass with dependence of meninges. Histologically,the tumor mainly consisted of cords of vacuolatedcells in an abundant myxoid and basophilic matrix. Thetumor cells expressed epithelial membrane antigen (EMA)but not glial fibrillary acid protein (GFAP), S-100 protein orcytokeratin. The neoplasm was diagnosed chordoid meningiomagrade II of the Word Health Organization (WHO) (AU)

X-linked lymphoproliferative disease associated with hypogammaglobulinemia and growth-hormone deficiency.

X-linked lymphoproliferative disease is a rare immunodeficiency disorder characterized by extreme vulnerability to Epstein-Barr virus, dysgammaglobulinemia, and very high incidence of lymphoma. Growth-hormone deficiency has been described in rare cases to be associated with certain immunodeficiencies, such as X-linked agammaglobulinemia. We report a first case with X-linked lymphoproliferative disease associated with hypogammaglobulinemia and growth-hormone deficiency, which was confirmed by SAP gene mutation. The patient's mutation is novel. He is also the first patient with X-linked lymphoproliferative disease to be reported from Saudi Arabia. The patient's Btk expression and BTK gene were normal. Patients with hypogammaglobulinemia and GH deficiency should be considered to have not only X-linked agammaglobulinemia, but also X-linked lymphoproliferative disease.

Dysgammaglobulinaemia in the elderly--a review and case studies.

An understanding of the possible causes of dysgammaglobulinaemia in the elderly helps to direct further investigation to establish a diagnosis. In this review we provide brief case studies to illustrate some of the disorders associated with dysgammaglobulinaemia in the elderly. We consider both hypergammaglobulinaemia (polyclonal, characteristic of chronic inflammatory disorders or autoimmunity, and monoclonal, often with an associated malignant disorder) and hypogammaglobulinaemia (including immunodeficiency, immune paresis secondary to malignancy and protein loss). Where dysgammaglobulinaemia is noted in the elderly the most useful laboratory tools to help discern the pathogenesis are serum and urine electrophoresis, autoantibody investigations and measurement of liver and renal function.

Molecular and cellular pathogenesis of X-linked lymphoproliferative disease.

X-linked lymphoproliferative disease (XLP) is an inherited immune defect caused by mutations in the Src homology 2 domain-containing gene 1A, which encodes the adapter protein, signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). SAP is expressed in T cells, natural killer (NK) cells, and NKT cells, where it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK-T-B-antigen, and CD2-like receptor-activating cytotoxic T cells. SAP also binds to the Src family tyrosine kinase Fyn and recruits it to SLAM, which leads to the generation of downstream phosphotyrosine signals. While the roles of the SLAM family receptors are only beginning to be understood, experiments suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. Thus, in XLP patients who lack functional SAP, the SLAM family receptors may not signal properly. This property likely contributes to the phenotypes of XLP, including fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia. Further studies of SAP and the SLAM family receptors will provide insights into XLP and elucidate the signaling events regulating lymphocyte ontogeny and function.

Serum IgE level in malnutrition.

UNLABELLED: Infections and malnutrition remain the main causes of infant mortality in developing countries. In protein-calorie malnutrition, immunologic responses are affected, which often facilitates infections. However, the presence of asthma and allergic rhinitis are not commonly recognized in malnourished individuals. The aim of this study was to evaluate serum IgE values in children with primary moderate protein-calorie malnutrition. METHODS: The level of IgE in peripheral blood of 18 children between 2 and 4 old with moderate protein-calorie malnutrition and without associated parasitic infestation was compared with that of 15 well nourished children of similar age. IgE serum levels were measured by an immunoenzymatic method. RESULTS: The median level of serum IgE in malnourished children was 69.30 ng/ml while the control group showed a mean level of 95.97 ng/ml. This difference was significant (p < 0.01). CONCLUSION: Malnourished children show decreased serum IgE levels. This might be one of the adaptive mechanisms of malnutrition employed in an attempt to use energy and protein reserves for growth and other functions. Our results are coherent with the decrease in IgE mediated reactions in malnourished patients.

Improved dysgammaglobulinaemia in congenital rubella syndrome after immunoglobulin therapy: correlation with CD154 expression.

UNLABELLED: A boy with congenital rubella syndrome developed dysgammaglobulinaemia with elevated serum levels of IgM. CD154 was not induced on his peripheral blood mononuclear cells when rubella virus RNA was detected in his throat swabs and peripheral blood by reverse transcriptase polymerase chain reaction. Following intravenous immunoglobulin therapy, improvement of immunoglobulin abnormalities, disappearance of rubella virus and normalisation of CD154 expression were demonstrated. CONCLUSION: These findings implicate the efficacy of intravenous immunoglobulin therapy for dysgammaglobulinaemia in congenital rubella syndrome and a role of CD154 for a prolonged virus infection.

Stressed rats fail to expand the CD45RC+CD4+ (Th1-like) T cell subset in response to KLH: possible involvement of IFN-gamma.

Exposure to stressors effects various aspects of immune function, including the in vivo antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-KLH (keyhole limpet hemocyanin) IgM and IgG. The mechanisms responsible for this suppression are currently unknown. Previous work has suggested changes in CD4+ T cells could be important. We report here that exposure to IS results in a reduction in Con A-stimulated IFN-gamma levels in mesenteric lymphocytes and splenocytes taken immediately after IS termination. In addition, IS exposure prevents the KLH-induced increase in the number of CD45RC+CD4+ T cells (Th1-like) in both the mesenteric lymph nodes and the spleen 4 days after immunization. The failure of KLH to expand the CD45RC+CD4+ subset could be due to the stress-induced reduction in IFN-gamma levels reported in cells taken at the time of immunization. Implications of these findings as a mechanism for the decrease in the in vivo antibody response previously reported is discussed.

DNA mutation induced in the sequence upstream of the secreted MYU C-terminal coding sequence by ultraviolet irradiation in the cell line of Bloom's syndrome.

Selective IgM deficiency is commonly found in Bloom's syndrome (BS). We reported that membrane-bound mu (micron(s)) mRNA was well transcribed but secreted mu (microseconds) mRNA was not, although there was no mutation or deletion in the sequence including the microseconds C-terminal coding sequence in the patients with BS. Furthermore, we have shown previously, preferential damage to IgM production by ultraviolet (UV) irradiation of the cells of the patient. In the study described here, mutation in the sequence which is upstream of the 5' end of the microseconds C-terminal coding sequence was induced by UV irradiation in the lymphoblastoid cell line (LCL) of BS patient. These results suggest that abnormal repair of DNA damage is present in this LCL, and that preferential damage to IgM production by UV irradiation in this LCL may be due to the abnormal repair of DNA damage.

Clonal imbalances of serum immunoglobulins after allogeneic bone marrow transplantation: an analysis by high-resolution two-dimensional gel electrophoresis.

The clonality pattern of immunoglobulins (Igs) produced after allogeneic bone marrow transplantation (BMT) was studied by high-resolution two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) of serum samples and purified Igs. With this technique, the light (L) chain of a monoclonal Ig usually appears as a single spot. Thus, the degree of clonal diversity of the functional B cells can be appreciated by the electrophoretic pattern of the serum L chains. Furthermore, 2D-PAGE allows a semi-quantitative determination of prominent Ig clones according to the size of L chain spots. We found that serum electrophoretograms of 8/19 patients after BMT (5-9 months) revealed L chain patterns which were similar to those of normal polyclonal Igs, that is, less than five distinguishable small spots among a cloud-like indiscrete L chain spots region ('polyclonal' pattern). A spectrum of clonal abnormalities was observed on the electrophoretograms of 11/19 patients: in five patients, multiple small L chain spots (corresponding to Ig concentrations between 0.2 and 2 g/l) were detected ('oligoclonal' pattern), whereas in six others, 'typical' monoclonal Igs (Ig concentrations > 2 g/l) were observed with (3/19 patients) or without (3/19 patients) multiple small clonal components. Sequential analysis of serum obtained from patients at different times after BMT revealed that imbalanced clonal reconstitution was transient and evolved towards apparently normal polyclonal Ig production. Our observations show that the development of clonal 'gammopathies' after BMT is a frequent, but not obligatory phenomenon. It may reflect a transient restriction of the B cell repertoire either through a limited outgrowth of precursor cells or through selective antigenic pressures.

Iatrogenic IgG2 deficiency in a leukaemic child. A case report.

A girl with acute non-lymphoblastic leukaemia was treated with immunosuppressive chemotherapy. After cessation of therapy she had three consecutive episodes of infection due to Streptococcus pneumoniae from which she recovered and was shown to have developed a combined deficiency of both IgG2 and IgG4. The patient eventually relapsed and died 3 years after the initial diagnosis. The importance of measuring IgG subclasses in patients treated with immunosuppressive chemotherapy is discussed.

[Severe leukopenia and thrombocytopenia and transient acquired hypogammaglobulinemia in a patient with infectious mononucleosis]. / Leucopenia y trombocitopenia intensas e hipogammaglobulinemia adquirida transitoria en un paciente con mononucleosis infecciosa.

A 30-year-old male with infectious mononucleosis by the Epstein-Barr virus who presented severe neutropenia and thrombocytopenia and type IgG acquired transitory hypogammaglobulinemia as complications during the acute period of the disease is presented. Although the etiopathogenesis of these phenomena is usually associated with an autoimmune basis, the antiplatelet and antileukocyte antibodies were negative. A bibliographic revision of the hematologic alterations of this disease was carried out and it was observed that the combination of the complications described has not been previously referred, thus, the present case may be the first observation with these characteristics.

[Quantitative, functional and cytogenetic characteristics of lymphocytes and various indicators of immunity in persons participating in the decontamination work at the Chernobyl nuclear power plant]. / Kolichestvennaia, funktsional'naia i tsitogeneticheskaia kharakteristika limfotsitov i nekotorye pokazateli immuniteta u lits, prinimavshikh uchastie v avariino-vosstanovitel'nykh rabotakh na Chernobyl'skoi AES.

Immunologic and cytogenetic investigations conducted in subjects, who had been engaged in liquidation of consequences of the Chernobyl NPS catastrophe, during the first months after their work was finished, showed decreased content of large granulo-containing lymphocytes and serum IgM in the blood, their levels were completely recovered 3 years later. A complex of unfavourable factors attending radiation (stress, changes in the way of life, chemical actions etc.) played an important role in the genesis of these changes.

[Evaluation of various immunologic parameters in patients treated by continuous ambulatory peritoneal dialysis (CAPD)]. / Ocena niektórych parametrów immunologicznych u chorych leczonych ciagla ambulatoryjna dializa otrzewnowa (CADO).

The authors investigated some immunologic parameters in 17 patients treated with CAPD during 11.0 +/- 6.8 months. There were no disturbances in humoral immunity. In cell-mediated immunity we observed only skin anergy specially in patients with high peritonitis rate. In this group we observed lower concentration of IgG, C3 complement and fibronectin in peritoneal effluent.

Deficiency of IgG subclasses and IgA, and elevation of IgE in children with a past history of bacterial meningitis.

Of 44 children who recovered from an attack of bacterial meningitis, 3 (7%) were found to have IgG subclass deficiency, 5 (11%) had IgA deficiency and 22 (50%) had raised IgE levels. These results suggest that immunoglobulin abnormalities may be an important predisposing factor in some cases of bacterial meningitis.