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Results for “Immunologic Deficiency Syndromes”

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At least 235 records · Page 13Linked to original sources
PubMed2000

Lymphotoxin-alpha-dependent spleen microenvironment supports the generation of memory B cells and is required for their subsequent antigen-induced activation.

Lymphotoxin alpha-deficient (LTalpha-/-) mice show dramatically reduced IgG responses after either primary or secondary immunizations with sheep red blood cells (SRBC). When splenocytes from SRBC-primed wild-type donor mice were infused into irradiated naive wild-type recipient mice, they generated a robust memory IgG response, but not when infused into LTalpha-/- recipients, indicating that the microenvironment that develops in LTalpha-/- mice is incompetent to support the activation of this memory response. When irradiated wild-type mice were reconstituted with splenocytes from primed LTalpha-/- donors and then challenged with the same immunizing Ag, no memory response was observed, indicating further that memory cells could not be generated in the LTalpha-/- environment. To address which lymphocyte subsets were impaired in the LTalpha-/- mice, we performed reconstitution experiments using a hapten/carrier system and T cells and B cells from different primed donors. There was no detectable defect in either the generation or expression of memory T cells from LTalpha-/- donors. In contrast, B cells were not primed for memory in the microenvironment of LTalpha-/- mice. Additionally, primed wild-type memory B cells could not express a memory IgG response in the LTalpha-/- microenvironment. Thus, splenic white pulp structure, which depends on the expression of LTalpha for its development and maintenance, is needed to support the generation of memory B cells and to permit existing memory B cells to express an isotype switched memory Ig response following antigenic challenge.

Animals↗
PubMed2000

Impaired affinity maturation in Cr2-/- mice is rescued by adjuvants without improvement in germinal center development.

Cr2-/- mice have an impairment in humoral immunity, as shown by the decrease in the Ab titers against T cell-dependent Ags and abnormalities in germinal center formation. Germinal centers are present, but they are decreased in size and number, indicating problems in their development. In this study, we investigated whether this abnormality in germinal center development is associated with problems in the establishment of optimal affinity maturation and the generation of memory B cells, processes closely related to the germinal center reaction. We immunized the Cr2-/- animals with different Ags with or without adjuvants. We showed that, when immunized without adjuvants, complement receptors are absolutely required for optimal affinity maturation. Although limited affinity maturation is elicited in the Cr2-/- Ab response, it is decreased as compared with normal animals. Memory B cell generation is also impaired. In the presence of adjuvants, germinal center development in the Cr2-/- mice is still abnormal, as demonstrated by their decreased size and number. Surprisingly, adjuvants establish optimal affinity maturation and partially restore the amount of Ab produced during the primary response and memory B cell generation. However, adjuvants cannot improve the ability of follicular dendritic cells to retain Ags in the form of immune complexes. These observations indicate that immunization with inflammatory Ags offset some of the immunological abnormalities found in the Cr2-/- mice and show that optimal affinity maturation in the Cr2-/- mice can be achieved in the absence of normal germinal centers.

Adjuvants, Immunologic↗
PubMed2003

Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency.

Defects in IL-12 production or IL-12 responsiveness result in a vulnerability to infection with non-viral intracellular organisms, but the immunological mechanisms responsible for this susceptibility remain poorly understood. We present an immunological analysis of a patient with disseminated Salmonella enteritidis and a homozygous splice acceptor mutation in the IL-12Rbeta1-chain gene. This mutation resulted in the absence of IL-12Rbeta1 protein on PBMC and an inability of T cells to specifically bind IL-12 or produce IFN-gamma in response to either IL-12 or IL-23. The accumulation of memory (CD45R0(high)) CD4 T cells that were CCR7(high) (putative central memory cells) was normal or increased for age. Central memory CD4 T cells of the patient and age-matched controls were similar in having a low to undetectable capacity to produce IFN-gamma after polyclonal stimulation. In contrast, the patient had a substantial decrease in the number of CCR7(neg/dull) CD45R0(high) memory CD4 T cells (putative effector memory cells), and these differed from control cells in having a minimal ability to produce IFN-gamma after polyclonal stimulation. Importantly, tetanus toxoid-specific IFN-gamma production by PBMC from the patient was also significantly reduced compared with that in age-matched controls, indicating that signaling via the IL-12Rbeta1-chain is generally necessary for the in vivo accumulation of human memory CD4 T cells with Th1 function. These results are also consistent with a model in which the IL-12Rbeta1 subunit is necessary for the conversion of central memory CD4 T cells into effector memory cells.

Adolescent↗
PubMed2003

Memory phenotype of CD8+ T cells in MHC class Ia-deficient mice.

B6.K(b-)D(b-) mice are devoid of class Ia but express normal levels of class Ib molecules. They have low levels of CD8 T cells in both the thymus as well as peripheral T cell compartments. Although the percentage of splenic CD8 alpha alpha T cells is increased in these animals, approximately 90% of CD8 T cells are CD8 alpha beta. In contrast to B6 animals, most of the CD8 T cells from these mice have a memory phenotype (CD44(high)CD122(high) CD62L(low)) including both CD8 alpha beta and CD8 alpha alpha subsets. In the thymus of B6.K(b-)D(b-) animals, there is a decrease in the percentage of SP CD8 T cells, although most are CD44(low), similar to that seen in B6 mice. The spleens from day 1-old B6 and B6.K(b-)D(b-) mice have a relatively high proportion of CD44(high)CD62L(low) CD8 T cells. However, by day 28 most CD8 T cells in B6 mice have a naive phenotype while in B6.K(b-)D(b-) mice the memory phenotype remains. Unlike CD44(high) cells that are found in B6 animals, most CD44(high) cells from B6.K(b-)D(b-) mice do not secrete IFN-gamma rapidly upon activation. The paucity of CD8 T cells in B6.K(b-)D(b-) mice might be due in part to their inability to undergo homeostatic expansion. Consistent with this, we found that CD8 T cells from these animals expand poorly in X-irradiated syngeneic hosts compared with B6 CD8 T cells that respond to class Ia Ags. We examined homeostatic expansion of B6 CD8 T cells in single as well as double class Ia knockout mice and were able to estimate the fraction of cells reactive against class Ia vs class Ib molecules.

Animals↗
PubMed2003

Role of MHC class I in immune surveillance of mitochondrial DNA integrity.

Mitochondrial DNA is subject to increased rates of mutations due to its proximity to the source of reactive oxygen species. Here we show that increased MHC class I (MHC I) expression serves to alert the immune system to cells with mitochondrial mutations. MHC I is overexpressed in fibroblasts with mitochondrial dysfunction from patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and in lymphocytes from purine nucleoside phosphorylase-deficient immune-deficient mice with mitochondrial DNA deletions. Consistent with a role of MHC I in the elimination of cells containing mitochondrial DNA mutations, mice deficient in MHC I accumulate mitochondrial DNA deletions in various tissues. These observations in both mice and humans suggest a role for the immune system in preventing reversion of mitochondrial DNA back into a parasitic state following deleterious mutations affecting mitochondrial oxidative phosphorylation.

Animals↗
PubMed2003

Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice.

STAT5 has previously been reported to be dispensable for the maintenance of tolerance in vivo. However, in examining hemopoiesis in mice lacking both isoforms of STAT5, STAT5A, and STAT5B, we noted that a subset of these mice demonstrated dramatic alterations in several bone marrow progenitor populations concomitant with lymphocytic infiltration of the bone marrow. In addition, cellular infiltration affecting the colon, liver, and kidney was observed in these mice. Survival analysis revealed that STAT5A/5B(-/-) mice exhibited early death. The increased mortality and the pathology affecting multiple organs observed in these mice were abrogated on the recombination-activating gene 1(-/-) background. In light of the similarities between STAT5A/5B-deficient mice and mice unable to signal through the IL-2R, we hypothesized that the tolerizing role of STAT5A/5B was triggered via activation of the IL-2R. In agreement with this, we found that IL-2Rbeta chain-deficient mice exhibited similar hemopoietic abnormalities. Because IL-2 signaling is thought to contribute to tolerance through maintenance of a CD4(+)CD25(+) regulatory T cell population, we examined these cells and observed a numerical reduction in STAT5A/5B(-/-) mice along with a higher rate of apoptosis. These data provide strong evidence for a requirement for STAT5 in the maintenance of tolerance in vivo.

Adoptive Transfer↗
PubMed2005

IL-12 is required for induction but not maintenance of protective, memory responses to Blastomyces dermatitidis: implications for vaccine development in immune-deficient hosts.

Cellular immunity mediated by T lymphocytes, in particular CD4(+) and CD8(+) type 1 (T1) cells, is the main defense against pathogenic fungi. IL-12 initiates T1 cell development and cell-mediated immunity, but it is unclear whether IL-12 contributes to the maintenance of an antifungal T1 response. In this study, we addressed the role of IL-12 for vaccine-induced memory T cell development against experimental pulmonary blastomycosis. CD4(+) T cells absolutely required IL-12 to control a live genetically engineered attenuated strain of Blastomyces dermatitidis given s.c. as a vaccine, whereas CD8(+) T cells were significantly less dependent on IL-12. Despite differential dependency of T cell subsets on IL-12 during vaccination, neither subset acquired memory immunity in the absence of IL-12. In contrast, adoptive transfer of immune CD4 T cells from wild-type mice into IL-12(-/-) mice showed that CD4(+) T1 memory cells sustained a T1 cytokine profile and remained protective over a period of 6 mo posttransfer. Similarly, memory CD8 cells elicited in IL-12(-/-) mice with killed yeast and transient rIL-12 treatment (during vaccination) remained durable and protective after animals were rested for 3 mo. In conclusion, these studies demonstrate that once CD4 and CD8 cells have acquired a protective T1 phenotype they no longer require the presence of IL-12 to maintain antifungal protective memory.

Animals↗
PubMed1991

Biologic response modifiers in primary immunodeficiency disorders.

OBJECTIVE: To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders. DATA SOURCE: Relevant articles were identified through a search of MEDLINE using the following indexing terms: primary immunodeficiencies (and subclassifications), and human immunomodulators (and subclassifications). STUDY SELECTION: Articles were critically reviewed and included if relevant. DATA SYNTHESIS: The primary immunodeficiency disorders are classified according to functional abnormalities, specifically, abnormalities in early cellular maturation, differentiation, regulatory cell function, enzymatic function, and cytokine responses. Such a classification clarifies the potential role of biologic response modifiers in primary immunodeficiency disorders. Intravenous gammaglobulin and histamine-2 (H2)-receptor blockers modify regulatory cell function; retinoids modify abnormal cellular differentiation, gene transfer and enzyme replacement can be applied in disorders characterized by specific functional gene abnormalities; and interferons modify abnormal cytokine responses. Interleukin-2, thymic hormones, transfer factor, and levamisole appear to affect multiple functional defects. CONCLUSIONS: Biologic response modifiers are currently important ancillary tools in the treatment of immunodeficiency disorders, and their therapeutic role will become even more important in the future. Multi-center cooperative trials of new and existing agents are needed to fully define their roles and efficacy in the treatment of these disorders.

Cytokines↗
PubMed1999

Availability of immune globulin intravenous for treatment of immune deficient patients--United States, 1997-1998.

Immune globulin intravenous (IGIV) is a lifesaving treatment for patients with primary immunodeficiency. Since November 1997, a shortage of IGIV has existed in the United States. In 1998, the Food and Drug Administration (FDA) required pharmaceutical companies to increase the frequency of reporting on IGIV distribution from biannually to monthly; in addition, FDA facilitated IGIV distribution and informed clinicians about the ongoing shortage. To assess the impact of the IGIV shortage on patient care, in 1998 the Immune Deficiency Foundation (IDF) surveyed physicians caring for immunodeficient patients about whether they have had difficulty obtaining IGIV, measures they have taken because of the shortage, and the effect of the shortage on their patients. This report summarizes data reported to FDA and data obtained from the IDF survey and provides recommendations for IGIV use during the shortage.

Drug Utilization↗
PubMed1999

[Immunology in medical practice. XVIII [correction of XVII]. Children with recurrent airway problems: asthma is not always the cause.

Three children, two boys aged 16 and 11 years and a girl aged 16 years, with symptoms resembling asthma had been treated for years with inhaled corticosteroids and beta 2-sympathicomimetics without satisfactory results. It was found that the antibody production after vaccination with 23-valent pneumococcal vaccine was impaired. The symptoms diminished during maintenance treatment with antibiotics in two children and with intravenous immunoglobulins in one. In patients with recurrent respiratory problems, but no specific history of asthma, immunological investigation is warranted, especially in patients whose 'asthma' is accompanied by respiratory infections. When treated for their immunodeficiency these patients show remarkable improvement and the need for steroids often disappears.

Adolescent↗
PubMed2000

B cell development and primary immunodeficiencies with hypogammaglobulinemia.

The differentiation of B cells along the pathway of B cell development has been well characterized. In the bone marrow, the differentiation from pro-B cells to immature B cells can be defined by several surface antigens, such as a surrogate light chain. Immature B cells become mature B cells and then circulate in the peripheral blood as naive B cells. In the peripheral lymphoid tissues, naive B cells differentiate into memory B cells, which express the CD27 molecule, or plasma cells. Primary immunodeficiencies with hypogammaglobulinemia are caused by defects of the specific molecules which are needed for the B cell differentiation. Recent studies of the genes responsible for such immunodeficiencies have clarified B cell development as well as their pathogenesis. We discuss here the molecules affecting the B cell development and primary immunodeficiencies with hypogammaglobulinemia.

Agammaglobulinemia↗
PubMed2001

[Diagnosis and differentiated treatment of secondary immunodeficiencies].

AIM: To evaluate alterations in the immune system (IS) in patients with different forms of secondary immunodeficiency and design of differentiated programs of reestablishment of defective functions depending on pathogenetically important type of deficiency of immunocompetent cells. MATERIALS AND METHODS: Clinicoimmunological examination was made in 678 patients with complicated course of infectious-inflammatory diseases. Immunotropic medicines and physicochemical impacts were used in accordance with types of disorders in the system of immune homeostasis. RESULTS: There was a pathogenetic heterogeneity of IS disorders in complicated course of infectious-inflammatory diseases: generalized forms of infection (bacterial shock, sepsis) are in 75% of cases associated with deficiency of effector functions of peripheral blood polymorphonuclear leukocytes of the second-third degree, progressive fall in production of IgG immunoglobulins (42%), cellular-humoral immunodeficiency (92%). In lingering acute inflammatory diseases activation of phagocytosis occurred in 30%, IgG and/or IgM rise was in 50%, phagocytic function deficiency occurred in 48%, low production of immunoglobulins in 24%, humoral-cellular immunodeficiency in 62%. Purulent infection is associated with secondary cellular-humoral immunodeficiency, lowering of the immunoregulatory index (47%), phagocytic function deficiency (up to 35%), hyperproduction of IgM. Recurrent bacterial-viral diseases form in immunocompromised patients with T-lymphocytopenia (56%) and cellular-humoral immunodeficiency (30%). CONCLUSION: Protracted chronic inflammatory diseases are characterized by variability of changes in the immune systems. Combined types of disorders were found in 52% of the examinees. Pathogenetic heterogeneity of the disorders are determined by concomitant and previous diseases, occupational hazards and intoxication, environmental conditions, etc. CONCLUSION: Immunocorrective therapy in secondary immunodeficiency is conducted with allowances for pathogenetically essential types of disorders in the system of immune homeostasis, clinical variant of complication of inflammatory process under control of immunogram.

Acute Disease↗
PubMed1984

Primary immune disorders in children and their diagnosis.

The clinical features and laboratory findings of 18 children with various primary immune deficiencies and their immunologic diagnosis have been discussed. In 3 patients of ataxia telangiectasis human foetal thymus transplantations have been performed with some success.

Adolescent↗