Inflammation & Allergy-Drug Targets (v.11, #3)

Adult hematopoietic stem cells (HSC) continuously replenish the blood with immune and blood cells with a finite life span, from the bone marrow (BM) reservoir of immature and maturing leukocytes. Regulation of HSC migration and development is essential for their function and blood cell production. These diverse and multiple states require a tight regulation to efficiently address host defense and repair requirements. Numerous recent studies disclose a central role for bone related cells in regulation of HSC and hematopoiesis. During ontogeny HSC home and seed the fetal BM in the last gestation period when the bone is already ossified. Ossification involves bone forming osteoblast- and bone degrading osteoclast activity and is considered essential for the formation of BM cavities and hematopoiesis. This synchronized association implies the need for active bone cells and bone turnover for HSC regulation. Osteoblastic cells and SDF- 1+/nestin+ reticular adventitial and CAR cells are crucial for regulation of HSC lodgment, self-renewal and function. Bone resorbing osteoclasts regulate bone turnover and progenitor cell detachment and release from the BM. Sympathetic signals from the nervous system activated by circadian rhythms or stress conditions control both bone turnover and HSC migration and development. In this review we discuss pathways and mechanisms involved in this orchestrated regulatory network. A special focus is made on the pivotal role of the SDF-1/CXCR4 axis as a determinant of HSC fate. Inflammation, DNA damage, cytokine mobilization, microgravity and aging are discussed as specific physiologic and pathologic events entailing dysregulation of the tightly balanced Bone-Brain-Blood triad.

Osteoimmunology is an interdisciplinary field addressing the interplay between the skeletal and the immune system. A substantial body of evidence demonstrated the existence of two-way regulatory mechanisms that affect both systems, placing them in much closer association to each other than one could ever predict. Inflammatory diseases have long been known to induce alterations in bone metabolism, and inflammatory cytokines play prominent roles in the control of bone resorption, representing communication pathways bridging the two systems. Osteoclasts are particularly linked to the immune cells because they belong to the monocyte/macrophage family, have tight relationships with B and T cells, and differentiate in response to RANKL which is also produced by lymphocytes and regulates lymphopoiesis. Osteoclasts are negatively regulated by cytokines and other factors known for their anti-inflammatory and immune regulatory activity. Finally, they express immune co-receptor typical of immune cells which are indispensable for their differentiation, thus leading to the hypothesis that osteoclasts are immune cells themselves. The underlying principle why an immune cell is required to resorb bone has not yet been elucidated. Data from early literature suggest that the bone matrix could trigger an innate immune response activating giant cells that could destroy large bone areas because of their unique property of resorbing bone extracellularly. Bone resorption could though be prevented by the physical barrier made by osteoblasts and lining cells, whose retraction would be required to give access to osteoclasts when specific pathways signal their precursors to differentiate and mature osteoclasts to reach the uncovered bone surface.

Inflammation-Associated Changes in Bone Homeostasis by Carina Scholtysek (188-195).
Bone is a dynamic tissue undergoing constant remodelling and repair. Its homeostasis is regulated by a coordinated process executed by bone forming and bone resorbing cells. Apart from being a major component of the locomotive system, bone provides protection for internal organs and represents a main mineral storage. Furthermore, it houses the haematopoietic system and is hence essential for the body’s immune response. In turn, the innate and adaptive immune system itself, critically affect bone homeostasis. This is most evident during chronic inflammatory diseases, such as Rheumatoid Arthritis, where bone mass is critically reduced. Recently the field of osteoimmunology, focusing on this crosstalk between the immune system and bone homeostasis, has gained increasing attention. This review will highlight cellular and molecular mechanisms linking the innate and adaptive immune response to bone biology and provide an overview about involved cytokines and cells. Moreover, chronic inflammation and its consequences for bone turnover are discussed.

The maintenance of bone homeostasis is tightly controlled, and largely dependent upon cellular communication between osteoclasts and osteoblasts, and the coupling of bone resorption to bone formation. This tight coupling is essential for the correct function and maintenance of the skeletal system, repairing microscopic skeletal damage and replacing aged bone. Cells in osteoclast and osteoblast lineages communicate with each other through diffusible paracrine factors, cell-cell contact, and cell-bone matrix interaction. Osteoclast-osteoblast communication occurs in a basic multicellular unit (BMU) at the initiation, transition and termination phases of bone remodeling. At the initiation phase, hematopoietic precursors are recruited to the BMU. These precursors differentiate into osteoclasts following interactions with osteoblasts, which express and/or secrete ligands as RANK-L and OPG. Subsequently, the transition from bone resorption to formation is mediated by osteoclast-derived ‘coupling factors’, which direct the differentiation and activation of osteoblasts in resorbed lacunae to refill it with new bone. Signals derived from molecules released from the resorbed bone matrix, as TGF-beta and bidirectional signaling generated by interaction between ephrinB2 on osteoclasts and EphB4 on osteoblast precursors facilitates the transition. At the termination phase, bone remodeling is completed by osteoblastic bone formation and mineralization of bone matrix. The research steps that brought to the present knowledge are summarized in this review.

In mammals, hematopoietic stem cells (HSCs), which give rise to all blood cells and their progenies, including immune cells are controlled by special microenvironments, termed niches in the bone marrow during homeostasis and infection. However, the identity, nature and function of these niches remain unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (termed endosteal niche). However, recent studies suggest that only a small number of HSCs reside in the endosteal niche. In contrast, many HSCs are shown to be in contact with endothelial cells in the marrow. In addition, recent studies suggest that primitive mesenchymal cells, including CXCL12-abundant reticular (CAR) cells and Nestin-expressing cells, which have the ability to differentiate into adipocytes as well as osteoblasts act as niches for HSCs. Here we review candidate niches for HSCs in the bone marrow controlling hematopoiesis and chronic inflammation.

objective: In this paper, we reviewed plants being effective in treatment of BPH for the purpose of finding new sources of pharmaceutical agents. Methods: All pertinent literature databases were searched. The search keywords were plant, herb, herbal therapy, phytotherapy, benign prostatic hyperplasia, BPH, and prostate. All of the human, animal and in vitro studies were evaluated. Results: According to the studies, some of the substantial effective constituents of the plants in treatment of BPH are oenothein B, icaritin, xanthohumol, diarylheptanoid, 2,6,4'-trihydroxy-4-methoxybenzophenone, emodin, fatty acids, atraric acid, n-butylbenzene-sulfonamide, curbicin, theaflavin-3,30-digallate, penta-O-galloyl-b-D-glucose, lycopene, sinalbin, β-sitosterol, secoisolariciresinol diglucoside, genistein, apigenin, baicalein, and daidzein. Besides, Serenoa repens, Pygeum africanum, Curcubita pepo, and Urtica dioica as the most prevalent plants used to treat BPH. S. repens in human studies showed equivalent effectiveness to tamsulosin and in combination to U. dioica revealed equal effects to finastride with less side effects. Conclusion: There are numerous plants that have beneficial influence on BPH although the mechanisms of action in some plants are not well understood yet. Active ingredients of some of these plants are known and can be used as lead components for development of new effective and safe drugs.

Chronic granulomatous disease (CGD) is associated with defective function of the NADPH-oxidase system in conjunction with phagocytic defects which leads to granuloma formation and serious infectious complications. This is often associated with significant morbidity and mortality. The association of defective phagocyte function with other coincidental immune defects is unknown. Defects in innate pathways seen with CGD, including complement systems, and toll-like and dectin receptor pathways, have not been described before. We present the case of a 2-year old male patient hospitalized with recurrent pneumonia, a non-healing skin ulcer, necrotizing lung granulomas, and epididymo-orchitis. Defective neutrophil chemiluminescence was detected by dihydrorhodamine (DHR) testing. Further evaluation demonstrated characteristic molecular mutations of CYBB consistent with CGD. Immune evaluation demonstrated polyclonal hyperglobulinemia, but a greatly reduced mannose binding lectin (MBL) level. Six biallelic polymorphisms in MBL gene and its promoter were analyzed using Light CyclerTM Real-time PCR assay. The LXPA/LYPB haplotype of MBL was detected in our patient; the latter is the defective haplotype associated with low MBL levels. Due to the implications for innate immunity and the protection against bacterial, viral, and fungal infections provided by MBL, a deficiency of this protein may have disastrous consequences on the long term outcomes of CGD. MBL deficiency can also complicate other disorders affecting the immune system, significantly increasing the risk of infection in such patients. Further studies looking at the frequency and implications of MBL deficiency in CGD are needed.

The antiretroviral agent abacavir can cause hypersensitivity reaction (HSR) and the presence of HLA-B*57:01 is predictive of abacavir-HSR in Caucasian HIV-infected patients. However, abacavir-HSR also occurs in HLA-B*57:01 negative patients. In these patients, a safe diagnostic tool to dissect clinically suspected HSR against abacavir from adverse reactions against co-administered drugs is mandatory, and abacavir-ELISpot was evaluated. Peripheral blood mononuclear cells from 87 HIV patients were stimulated by abacavir and the production of interferon-γ to the ELISpot was determined. Abacavir treated patients with HSR [confirmed (n+5) or suspected (n+12)] vs without HSR (n+42) displayed significantly higher numbers of abacavir-specific cells (82.3±23.0 or 10.5±4.5 vs -0.5±1.0 spot forming cells per million PBMC, p < .005 each). In conclusion, we established the first abacavir-specific ELISpot. According to our preliminary data, a negative abacavir-ELISpot nearly excludes HSR against abacavir. Thereby the ELISpot may facilitate the decision to continue or withdraw abacavir treatment.

Chronic idiopathic urticaria is a common skin disorder characterized by recurrent appearance of wheals and/or angioedema for more than 6 weeks without an identifiable cause. Consensus guidelines suggest use of leukotriene receptor antagonists (montelukast or zafirlukast) in patients whose urticaria is resistant to antihistamines. Our objectives were (1) document the efficacy of montelukast in our patients, and (2) evaluate whether any clinical features or available laboratory investigations were associated with a response to montelukast. Patients who received montelukast between the years 2008-2011 (4-year period) were retrospectively identified from clinic letters. Clinical features and laboratory investigations were collected and analyzed. The primary end point was adequate control of disease without the need for systemic steroid therapy. 25 patients (10 males and 15 females; median age, 33 years; age range, 13-66 years) with an average duration of urticaria at 3.8 years received montelukast 10mg daily. 12 patients (48%) were better on montelukast with combined anti-H1 and anti-H2 therapy, with no statistical significance between median age and duration of urticaria between males and females. In 11 patients, montelukast had no effect and in 2 patients the urticaria worsened after montelukast was started. 15 patients had peripheral blood basopenia of which 5 patients responded to montelukast. Two patients had positive antinuclear antibody, 3 thyroid peroxidase antibodies and 4 with positive basophil histamine release. All 20 patients who had complement C3 and C4 levels done were within normal limits. Four of 6 patients (67%) with positive specific IgE responded to montelukast and combined anti-H1/H2 therapy. Almost half of our patients with chronic urticaria responded to montelukast and combined anti-H1 and anti-H2 therapy. We were unable to identify any clinical features or laboratory markers that were associated with a response to montelukast. Further studies are required to understand the failure of response of leukotriene inhibition in urticaria.

Probiotics survive in gastric environment competing with H. pylori. We studied probiotic “multistrain” administration in dyspeptics with H. pylori (placebo-controlled study). Forty patients with H. pylori (urea breath test - UBT - and IgG) were treated for 10 days with a mixture of 8 species of probiotics. Control group represented by 40 positive subjects received placebo. A second UBT and H. pylori stool antigen (HpSA) detection were performed after 1 month. Patients who remained infected were treated with triple therapy undergoing another UBT after 30 days. A second line therapy was administered in remaining positive patients. Statistics: Fisher’s exact probability and Student’s t tests. Thirteen out 40 patients using probiotics became negative, while controls remained positive, irrespectively of the initial UBT delta value. No difference in the eradication rates between the two groups was found (68%-71%). After second line therapy two patients remained positive.Thirteen out 40 patients using probiotics became negative, while controls remained positive, irrespectively of the initial UBT delta value. No difference in the eradication rates between the two groups was found (68%-71%). After second line therapy two patients remained positive. An adequate supplementation with probiotics might eradicate H. pylori.