Mona Hedayat

Proinflammatory cytokines in heart failure: double-edged swords.

Increased circulating and intracardiac levels of proinflammatory cytokines have been associated with chronic heart failure. Following an initial insult, the increased production of proinflammatory cytokines, including TNF-α, IL-6, IL-1, and IL-18, jeopardizes the surrounding tissue through propagation of the inflammatory response and direct effects on the cardiac myocyte structure and function. Cardiac myocyte hypertrophy, contractile dysfunction, cardiac myocyte apoptosis, and extracellular matrix remodeling contribute enormously to the development and progression of chronic heart failure. Despite the identification of efficacious pharmacological regimens and introduction of mechanical interventions, chronic heart failure remains among the leading causes of mortality worldwide. To introduce novel therapeutic strategies that modulate the inflammatory response in the context of the failing heart, it is of prime importance to determine the contributions of TNF-α, IL-6, IL-1, and IL-18 in mediating cardiac adaptive and maladaptive responses, as well as delineating their downstream intracellular signaling pathways and their potential therapeutic implications.

Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.

Targeting of Toll-like receptors: a decade of progress in combating infectious diseases

Toll-like receptors (TLRs) recognise highly conserved molecular structures, collectively known as pathogen-associated molecular patterns. In the past two decades, development and clinical implementation of TLR ligands-ie, chemically modified synthetic derivatives of naturally occurring ligands and fully synthetic small molecules-have been topics of intense research. Targeted manipulation of TLR signalling has been applied clinically to boost vaccine effectiveness, promote a robust T helper 1-predominant immune response against viral infection, or dampen the exaggerated inflammatory response to bacterial infection. Use of these new therapeutic molecules as adjuncts to conventional pharmacotherapy or stand-alone treatments might offer solutions to unmet clinical needs or could replace existing partly effective therapeutic strategies.

Prophylactic and therapeutic implications of toll‐like receptor ligands

The evolutionary conserved Toll‐like receptors (TLRs) are the first identified and best characterized pattern recognition receptors (PRRs) which discriminate self from nonself, providing an early and effective immune response against invading pathogens. The ever expanding knowledge of TLR signaling network make it one of the most promising therapeutic strategies to modulate the immune response in various human diseases. Immune modulating strategies based on TLR‐specific agonists elicit a potent immune response to adjuvant vaccine immunotherapy, cancers, allergic diseases, and chronic viral infections while minimizing the risk of uncontrolled provocation of systemic inflammatory response. Moreover, the contribution of TLR signaling in the pathogenesis of chronic noninfectious inflammatory and autoimmune diseases provides the rationale for the development and clinical implementation of TLR‐specific antagonists. At present, a few TLR‐specific agonists have been approved for both prophylactic and therapeutic applications, while the ongoing preclinical and clinical studies show promising results on various novel therapeutic molecules as an adjunctive to conventional pharmacotherapy or stand‐alone therapeutic strategy.  © 2010 Wiley Periodicals, Inc. Med Res Rev

A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton

Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASp-interacting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that links TCRs to the actin cytoskeleton in TCR-driven actin assembly. Further, they provide an explanation for similarities in the clinical phenotypes of WAS and DOCK8 deficiency.

Interleukin-23 receptor single nucleotide polymorphisms in ulcerative colitis. A study in Iranian populations.

BACKGROUND/OBJECTIVE Genetic factors seem to play an important role in the pathogenesis of ulcerative colitis (UC). Genome wide association studies showed a highly significant association between interleukin 23 receptor (IL23R) single nucleotide polymorphisms (SNPs) and Crohns disease; however, there are contrary results regarding the disease-modifying effects of IL23R variants in UC. This study was performed in a group of patients with UC to test the possible role of IL23R SNPs in conferring susceptibility or protection against the disease. METHODS The study was performed on 67 Iranian adult patients with UC and 78 healthy controls. Eight IL23R SNPs were genotyped, using real-time polymerase chain reaction (RT-PCR). The frequencies of alleles and genotype at each position were determined and compared between two groups of patients and controls. RESULTS The frequency of the T allele at position rs1343151 was significantly higher in the patient group, compared to the controls (P=0.018). The TT genotype at the same position was also significantly overrepresented in the patient group (P=0.02). There was no significant difference in alleles and genotype frequencies of other SNPs between patients and controls. CONCLUSIONS This study identified a new susceptibility locus associated with UC. Our findings provide further insight into the genetics of UC, which might be amenable to future therapeutic intervention.

Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre.

PURPOSE The aim was to describe the clinical manifestations, complications and long-term outcome of a cohort of Iranian patients with primary immune deficiency (PID). METHOD We retrospectively studied the demographic, clinical and immunological characteristics of the PID patients in a single tertiary centre, from January 1989 to July 2014. The patients were classified according to the International Union of Immunological Societies Expert Committee on PID. RESULTS 98 patients were diagnosed with and followed-up for 15 disorders. The mean age at onset and diagnosis and the diagnostic delay were 8±10, 14.2±13.1 and 6.1±7 years, respectively. Parental consanguinity rate was 57%. Predominantly Antibody Deficiency was the most common diagnosis (n=63), followed by congenital defects of phagocytes (n=16), combined immunodeficiencies (n=12), well defined syndromes (n=4) and defects in innate immunity (n=3). Recurrent sinopulmonary infection was the most common presentation. Active infections were treated appropriately, in addition to prophylactic therapy with IVIG and antimicrobials. Not all the patients were compliant with prophylactic regimens due to cost and unavailability. One SCID patient underwent successful bone marrow transplantation. The total mortality rate was 19% during the follow-up period (7.8±7.6 years). The mean age of living patients at the time of study was 23±11.7 years. CONCLUSIONS Physicians awareness of PID has been rising dramatically in Iran, ensuring an increasing number of patients being diagnosed and treated. More effective treatment services, including health insurance coverage and drug availability are needed to improve the outcome of PID patients.

Disorders of phagocytic cells

Patients with defects in phagocytic function are predisposed to intracellular microorganisms and typically have early dissemination of the infection. Recognition of the underlying disorder and aggressive antimicrobial therapy has been beneficial for the patients. Improved understanding of the pathophysiology of the disorder has also affected patient management by allowing specific, targeted immunomodulatory interventions. The cases in this chapter are not common but have had a significant impact on our understanding of the role of phagocytic cells in host defense. Conversely, understanding the role of the neutrophils and macrophages in infection has benefited not just the patients described in this chapter but also other patients with similar disease process.

Association of interleukin-4 gene polymorphisms with ischemic heart failure

BACKGROUND As of the potential immunomodulatory effects of interleukin-4 (IL-4) and its importance in inhibiting the production of proinflammatory cytokines by monocytes and activated T cells, the IL-4 gene polymorphisms were investigated in a group of patients with chronic heart failure due to ischemic heart disease. METHODS Forty three patients with ischemic heart failure (IHF) were enrolled in this study and compared with 139 healthy individuals. The allele and genotype frequency of 3 single nucleotide polymorphisms within the IL-4 gene were determined. RESULTS The frequency of the IL-4 -590/T allele in the patient group was significantly higher than in the control group (p < 0.0001). The most frequent genotypes in patients with IHF were IL-4 (-590) CC (p < 0.0001), IL-4 (-33) CC (p = 0.021), and IL-4 (-33) TT (p < 0.0001). The frequency of the following genotypes was significantly lower in patients compared to controls: IL-4 (-1098) TG (p = 0.035), IL-4 (-590) TC (p < 0.0001), and IL-4 (-33) TC (p < 0.0001). The most frequent IL-4 haplotypes in the patient group, which were significantly higher than in the control group, were TCC (p < 0.0001), TCT (p = 0.0242), and GCT (p = 0.0108) haplotypes. In contrast, the frequencies of the following haplotypes in the patient group were significantly lower than in the controls: GCC (p = 0.032), TTT (p = 0.0268), and TTC (p = 0.0399). CONCLUSIONS Certain alleles, genotypes, and haplotypes in IL-4 gene were over represented inpatients with IHF, which may, in turn, predispose individuals to this disease.

Primary hemophagocytic lymphohistiocytosis in Iran: report from a single referral center.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by fever, hepatosplenomegaly, and cytopenia, and widespread accumulation of lymphocytes and histiocytes, sometimes with hemophagocytosis, primarily involving the spleen, lymph nodes, bone marrow, and liver. HLH can either occur sporadically (secondary HLH) or as part of a familial syndrome (primary HLH), including familial HLH and the distinct immunodeficiency syndromes. Herein the authors report 6 Iranian patients with primary HLH and their outcome from a single tertiary-care center.