[Delay in diagnosis of common variable immunodeficiency: a paradigmatic case report]. / Ritardo di diagnosi di immunodeficienza comune variabile: un caso clinico emblematico.

This case report highlights the frequent delay in diagnosis of common variable immunodeficiency. The patient, 84 years old, had over 30 years of recurrent infections. At the first visit serum IgG were less than 134 mg/dl. From the review of previous examinations strong hypogammaglobulinemia was present for over 14 years.

[Genetic and environmental contribution to rheumatoid arthritis: a family study]. / Studio di una famiglia con elevata concordanza per artrite reumatoide: ruolo dei fattori genetici, ambientali e costituzionali.

We report on the HLA typing of three brothers (A, B, C) with rheumatoid arthritis (RA) and their six sons. This family is interesting for the full concordance for RA between parents. The aim of this study was the discovery of genetic and/or enviromental cofactors determining this absolute concordance.

Case report: safety and efficacy of tocilizumab in a patient with rheumatoid arthritis and chronic hepatitis C.

Tocilizumab is a monoclonal humanized anti-IL-6-receptor antibody used for the treatment of rheumatoid arthritis. The safety of tocilizumab in HCV patients is an open question. We report on safety and efficacy of tocilizumab in a 71-year-old female with rheumatoid arthritis and chronic hepatitis C. Monotherapy with tocilizumab (8 mg/kg every 4 weeks, i.v.) was prescribed after the discontinuation, determined by clinical inefficacy, of anti-TNF-alfa agents (adalimumab and, subsequently, etanercept). We have registered an optimal and rapid clinical response to tocilizumab with early remission (SDAI <3.3 since 4 weeks). The safety was good with no adverse events and maintenance, during a six-month followup, of normal liver enzymes. These data suggest a good safety profile of tocilizumab in patients with rheumatoid arthritis and chronic hepatitis C virus pathology.

[Rheumatoid arthritis: a typical multifactorial genetic disease: review of the literature]. / L'artrite reumatoide come modello di malattia genetica multifattoriale: una rassegna della letteratura.

Environmental factors can be triggers for the clinical appearance of rheumatoid arthritis in subjects with genetic susceptibility. Genetic factors account for 60% of disease susceptibility. This review is focused on the genetic and environmental basis of the susceptibility to arthritis.

Immunohematologic reconstitution in pediatric patients after T cell-depleted HLA-haploidentical stem cell transplantation for thalassemia.

To analyze immunohematologic reconstitution, particularly of natural killer (NK) cells, we evaluated 13 ß-thalassemia patients after 20 and 60 days and 1 year posttransplantation with T cell-depleted HLA-haploidentical stem cells. We assessed lymphocyte and bone marrow (BM) progenitor cell phenotype and differentiation capacity, spontaneous BM cytokine production, stromal cells, and stromal cell interleukin (IL)-7 production. A reduced clonogenic capability manifested at day +20. Patients had significantly lower CD4(+) T cells versus controls, mainly in the CD45RA(+)CD62L(+) subset. NKs were among the first lymphocytes to repopulate the peripheral blood. At day +60, an increase in primitive BM progenitor cells paralleled small increases in CD4(+), naïve CD4(+), and thymic naïve Th cells. A significant increase in CD4(+) and CD8(+) markers paralleled an increase in CD3⁻CD16(+) NKs, especially with full engraftment. In patients with stable mixed chimerism we observed very low levels of CD3(+) donor chimerism early after transplant that increased over time, but a stable population of high donor NK cells, suggesting a role of these cells on donor engraftment. Stromal cells secreted less IL-7 and displayed "macrophage-like" morphology. Patients initially manifested impaired stem/progenitor cell growth and differentiation capacity in parallel with altered T cell homeostasis and a reduced T cell naïve compartment. We hypothesize that T cell compartment damage partly arises from altered new T cell production from the hematopoietic stem/progenitor cells under stromal cytokine influence. NNK subset analysis might be useful for determining transplant outcome.

[Immunorecovery after prolonged HIV-related immunosuppression: opportunities of the new antiretroviral classes]. / Immunoricostituzione dopo prolungata immunosoppressione HIV-correlata: le opportunità dei nuovi schemi antiretrovirali.

Treatment of multi-drug experienced patients is an important concern in the management of HIV-1 disease, partially solved by the availability of new drugs acting at different phases of viral replication. Immune recovery during cART is linked both to the activity of antiviral drugs, as well as to the regenerative capability of thymus and bone marrow. We report a patient with a 22-year-old HIV-1 disease and an AIDS diagnosis for 15 years, with extensive resistance to all antiretroviral drugs, who never had treatment interruption, except for short spells due to adverse effects. This decision was supported by both findings elsewhere that interruptions of cART in experienced patients with advanced disease are strongly associated with more rapid disease progression and by our evaluation of his bone marrow activity. The colony-forming cells assay performed in the patient showed residual clonogenic capability, increased in vitro by addition of protease inhibitors and IL-2. A new therapeutic scheme including darunavir and maraviroc allowed dramatic changes leading both to a quick reduction in plasmatic viral load with an impressive immune reconstitution and an improvement in clinical conditions.

Altered clonogenic capability and stromal cell function characterize bone marrow of HIV-infected subjects with low CD4+ T cell counts despite viral suppression during HAART.

BACKGROUND: Inflammatory cytokines in bone marrow may impair hematolymphopoiesis in human immunodeficiency virus (HIV)-infected subjects who do not experience reconstitution of CD4(+) T cells despite suppression of virus replication while receiving highly active antiretroviral therapy (HAART) (immunological nonresponders). METHODS: Bone marrow samples from 12 immunological nonresponders receiving HAART were studied and compared with samples from 11 immunological responders. The mean CD4(+) T cell count (+/- standard deviation) was 174 +/- 68 cells/mm(3) and plasma HIV RNA levels had been <50 copies/mL for at least 1 year for individuals enrolled in the study. The clonogenic capability of bone marrow samples was evaluated using the colony forming cell assay and the long-term culture-initiating cell assay. CD34(+) cells from the colony forming cell assay were pooled for real-time polymerase chain reaction analysis of Fas and Fas ligand. Bone marrow cytokine production (interleukin-2 and tumor necrosis factor-alpha) and stromal interleukin-7 levels were analyzed by enzyme-linked immunosorbent assay in both groups. Flow cytometric analysis of CD4(+) and CD8(+) T cell subsets was performed. RESULTS: A reduced clonogenic capability and a decrease in the level of more primitive progenitor cells were observed in parallel with lower production of interleukin-2 and increased tumor necrosis factor-alpha levels. A significant upregulation of Fas and Fas ligand on CD34(+) cells and a higher stromal interleukin-7 production were observed. Impairment of the naive T cell compartment and persistent T cell activation were observed in peripheral blood. CONCLUSIONS: Samples from immunological nonresponders show reduced growth of in vitro colonies and an altered cytokine production in bone marrow. The cytokine pattern observed and the altered Fas and Fas ligand pathway may determine stem cell apoptosis and low CD4(+) cell recovery. These features, which are similar to those observed in HIV-infected subjects before starting therapy, persist despite treatment.

T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART.

OBJECTIVE: To investigate the pathogenesis of low CD4 T-cell count in subjects who are immunological non responders (InR) to HAART. DESIGN: Thirty-five HIV-positive subjects on HAART for at least 1 year, all with undetectable HIV-1 RNA, were studied. Patients were defined as InR according to a CD4 cell increase < 20% from CD4 cell baseline or CD4 cell count < 200/microl; subjects with a CD4 T-cell increase > 20% from baseline and a CD4 cell count > 200/microl were defined as immunological responders (IR). We performed a comprehensive study to characterize the immune response of InR. METHODS: The immunological phenotype of peripheral blood mononuclear cells, thymic naive T cells, T-cell receptor Vbeta repertoire, serum concentration of interleukin (IL)-7, the expression of IL-7Ralpha on naive and memory CD4 and CD8 T cells, and regulatory T cells (Treg) were studied. RESULTS: In InR a significant reduction (P < 0.0001) of naive and thymic naive CD4 T cells was associated with a reduced expression of IL-7Ralpha in both cell subsets, with an increased serum concentration of IL-7 was observed. Furthermore, an increased immune activation with a reduced Treg frequency and increased number of expansions of Vbeta families was observed. CONCLUSIONS: The reduced expression of IL-7Ralpha associated with the persistent immune activation and the alteration of Treg frequencies in part explains the low level of CD4 T cells observed in InR.

Immunodysregulation of HIV disease at bone marrow level.

Hematological abnormalities frequently occur in patients infected with HIV-1. Increasing evidence indicates that bone marrow (BM) suppression results from viral infection of accessory cells, with impaired stromal function and alteration of hematopoietic growth factor network. We investigated the effects of antiretroviral therapy on cytokine and chemokine production by BM cells and stromal cells, in a group of HIV-1-infected subjects before and during treatment. Compared with uninfected controls, an altered cytokine and chemokine production by BM cells has been observed before treatment, characterised by decreased IL-2 and elevated TNF-alpha, MIP-1alpha, MIP-1beta, and RANTES levels, along with a defective BM clonogenic activity. Antiretroviral therapy determined an amelioration of stem cell activity, a restoration of stromal cell pattern and functions, and an increased IL-2 production at BM level and a decrease of Fas expression on progenitor cells, in parallel with the diminution of TNF-alpha levels. HIV-1 protease inhibitors (PIs) may improve hematopoietic functions owing to their direct effects on the BM progenitor cells. Ritonavir and indinavir increased the colony growth of BM obtained either from HIV-1-infected patients or from normal individuals, in parallel with the normalization of functional and morphologic characteristics of stromal cells.

Changes in CCR5 and CXCR4 expression and beta-chemokine production in HIV-1-infected patients treated with highly active antiretroviral therapy.

The effect of highly active antiretroviral therapy (HAART) on the expression of CCR5 and CXCR4 HIV coreceptors and the production of the beta-chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta has been investigated in 30 HIV-1-infected individuals during 12-36 months of therapy. CCR5 expression was increased in both CD4 + and CD8 + subsets, whereas CXCR4 expression was upregulated only in CD4 + cells. CCR5 levels normalized during 36 months of therapy and positively correlated with the levels of memory, CD95 +, and HLA-DR + T cells. In contrast, the frequency of CXCR4-expressing cells was not significantly modified by HAART, although a downregulation was observed early after starting treatment. CXCR4 levels were significantly associated with the frequencies of naive T cells and negatively correlated with plasma viral load, CD95, and HLA-DR expression. An increased production of both spontaneous and lectin-induced RANTES, MIP-1alpha, and MIP-1beta was found at baseline in HIV-infected individuals. The spontaneous beta-chemokines production was not modified by 12 months of HAART, although a significant reduction was seen during the first months of therapy. A transient decrease of lectin-stimulated RANTES production was also observed, whereas the reduction of lectin-induced MIP-1alpha persisted for up to 12 months of therapy. In contrast, MIP-1beta secreted by phytohemagglutinin antigen-stimulated peripheral blood mononuclear cells progressively increased during HAART. In conclusion, our data indicate a normalization of CCR5 but not CXCR4 expression during suppressive therapy and changes in beta-chemokine production that may play a part in dictating the efficiency of viral infection and consequently the disease course.