Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis

Globally, more than 10 million people developed active tuberculosis (TB), with 1.4 million deaths in 2020. In addition, the emergence of drug-resistant strains in many regions of the world threatens national TB control programs. This requires an understanding of host-pathogen interactions and finding novel treatments including host-directed therapies (HDTs) is of utter importance to tackle the TB epidemic. Mycobacterium tuberculosis (Mtb), the causative agent for TB, mainly infects the lungs causing inflammatory processes leading to immune activation and the development and formation of granulomas. During TB disease progression, the mononuclear inflammatory cell infiltrates which form the central structure of granulomas undergo cellular changes to form epithelioid cells, multinucleated giant cells and foamy macrophages. Granulomas further contain neutrophils, NK cells, dendritic cells and an outer layer composed of T and B lymphocytes and fibroblasts. This complex granulomatous host response can be modulated by Mtb to induce pathological changes damaging host lung tissues ultimately benefiting the persistence and survival of Mtb within host macrophages. The development of cavities is likely to enhance inter-host transmission and caseum could facilitate the dissemination of Mtb to other organs inducing disease progression. This review explores host targets and molecular pathways in the inflammatory granuloma host immune response that may be beneficial as target candidates for HDTs against TB.

BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple (“uncomplicated”) increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.

Pathogenicity of severe fever with thrombocytopenia syndrome virus in mice regulated in type I interferon signaling

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease, which causes high fever, thrombocytopenia, and death in humans and animals in East Asian countries. The pathogenicity of SFTS virus (SFTSV) remains unclear. We intraperitoneally infected three groups of mice: wild-type (WT), mice treated with blocking anti-type I interferon (IFN)-α receptor antibody (IFNAR Ab), and IFNAR knockout (IFNAR−/−) mice, with four doses of SFTSV (KH1, 5 × 105 to 5 × 102 FAID50). The WT mice survived all SFTSV infective doses. The IFNAR Ab mice died within 7 days post-infection (dpi) with all doses of SFTSV except that the mice were infected with 5 × 102 FAID50 SFTSV. The IFNAR−/− mice died after infection with all doses of SFTSV within four dpi. No SFTSV infection caused hyperthermia in any mice, whereas all the dead mice showed hypothermia and weight loss. In the WT mice, SFTSV RNA was detected in the eyes, oral swabs, urine, and feces at 5 dpi. Similar patterns were observed in the IFNAR Ab and IFNAR−/− mice after 3 dpi, but not in feces. The IFNAR Ab mice showed viral shedding until 7 dpi. The SFTSV RNA loads were higher in organs of the IFNAR−/− mice compared to the other groups. Histopathologically, coagulation necrosis and mononuclear inflammatory cell infiltration in the liver and white pulp atrophy in the spleen were seen as the main lesions in the IFN signaling lacking mice. Immunohistochemically, SFTSV antigens were mainly detected in the marginal zone of the white pulp of the spleen in all groups of mice, but more viral antigens were observed in the spleen of the IFNAR−/− mice. Collectively, the IFN signaling-deficient mice were highly susceptible to SFTSV and more viral burden could be demonstrated in various excreta and organs of the mice when IFN signaling was inhibited.

Epidemiological and Histopathological Investigation of Sarcoptic Mange in Camels in Egypt

Mange has been considered one of the most common parasitic infestations among camels. It adversely impacts animal productivity and poses a risk to human health. Given the scarcity of available data about mange in camels, the current study focused on the prevalence of camel mange and its associated risk factors in Aswan Governorate, Egypt. Towards this end, a general visual inspection was conducted on camels (N = 210) in different markets and slaughterhouses in Aswan Governorate. Skin scrapings from suspect infected camels were also examined microscopically. Importantly, these findings were further checked and confirmed by histopathology on samples from suspected cases collected post-slaughter in abattoirs. The possible risk-associated factors, which include the camel’s age, sex and sampling season, were recorded and statistically analyzed. Interestingly, the data showed that a total of 100 camels (47.6%) were found exclusively infested by sarcoptic mange. Furthermore, the predominant histopathological changes included burrowing tunnel of mites in the skin, hyperkeratosis and acanthosisconsis of the epidermis, while the dermis showed hemorrhage, mononuclear inflammatory cell infiltration around the blood vessels and perifolliculitis. These major histopathological findings are consistent with sarcoptic mange. Furthermore, the statistical analysis of the possible associated risk factors, camel’s age (p = 0.006), gender (p = 0.032) and sampling season (p = 0.004), were all found to be significantly affected and related to the disease. In this regard, camels ≥2 years old were found at higher risk of infection (odds ratio (OR) = 2.75; 95% confidence interval (CI), 1.345 to 5.604) versus younger animals (OR = 0.36; 95 CI, 0.1784 to 0.743). Females had higher odds of exposure (OR = 2.02; 95% CI, 1.096 to 3.708) compared to males (OR = 0.50; 95% CI, 0.269 to 0.912). Moreover, the exposure to infection was reported higher in winter (OR = 2.30; 95% CI, 1.297 to 4.098) than in summer (OR = 0.43; 95% CI, 0.244 to 0.771). Collectively, our data provide novel epidemiological and histopathological support for sarcoptic mange being widespread among camels in the studied area. Sarcoptic mange is extremely contagious and zoonotic. Therefore, our baseline investigation indicates an urgent need for additional multicenter-studies to investigate the occurrence of this disease in camels and humans combined with the appropriate control measures of camel importation for combating this disease.

Nonclinical Safety Assessment of an Inhaled Formulation of Serelaxin: A Recombinant Human Protein in Rats and Cynomolgus Monkeys (Macaca fascicularis)

Serelaxin is a recombinant human relaxin-2 intended for cardiovascular indications. Inhalation was chosen as alternative route to intravenous to allow daily administration for chronic applications and home treatment. A total of 4 short-term studies were conducted in rats and cynomolgus monkeys with inhaled formulation of serelaxin at dose up to 10 mg/kg/d. All rats and cynomolgus macaques receiving serelaxin were exposed to the test item. One rat and approximately 50% of macaques developed immunogenicity, which did not appear to affect exposure. No adverse effect on respiratory function or systemic changes was noted. Both species developed similar microscopic lesions characterized by eosinophilic cell infiltration around bronchi; however, in the rat, this was more pronounced and extended to a perivascular location. In addition, in the rat, serelaxin showed eosinophilic crystalline material associated with macrophages in the alveoli and bronchioles. In macaques, serelaxin induced minimal macrophage infiltrates in alveoli and perivascular/peribronchiolar mononuclear cell infiltrations. The minimal airway eosinophilic/mononuclear inflammatory cell infiltrations were considered to be nonadverse in macaques due to the minimal severity and the lack of any other alterations in the lung parenchyma. In the rat, the presence of eosinophilic crystalline material and macrophage response, characterized as precipitated test article, was considered adverse.

Calcifying fibrous tumour: a rare case report of an exceptional lesion localized in retroperitoneum, mesentery and pelvis

Calcifying fibrous tumours are rare benign lesions affecting mostly children and young adults. A 17-year-old female presented with abdominal pain and abdominal distention. Physical examination revealed intra-abdominal mass occupying retro peritoneum and right iliac fossa. Excisional biopsy from peritoneum and mesentery were performed. Histopathologically, it was composed of hypocellular hyalinised collagenized stroma, spindle cells, psammomatous and dystrophic calcification and mononuclear inflammatory cell infiltration. Authors are here in reporting a case of calcifying fibrous tumour and discussing its clinical and morphological features with regard to the literature.

Kidney osteoclast factors and matrix metalloproteinase expression in a mice model of diet-induced obesity and diabetes

ABSTRACTThe role of RANKL/RANK/OPG system on bone remodeling is well known, and there is evidence that it is also important to cardiovascular and kidney pathology, although the underlying mechanisms are not elucidated so far. Thus, we investigated in a mice model of diet-induced obesity and diabetes if renal histopathological changes are associated with the expression of RANKL/RANK/OPG system and matrix metalloproteinases (MMPs). Three months old C57BL/6 mice were fed with control (AIN93M) or high-fat high sucrose (HFHS) diets for 21 weeks (CEUA/UFF #647/15). The HFHS group showed weight gain (+35%, P=0.0001), increased epididymal, inguinal and retroperitoneal fat pad weight (+121 %, P = 0.0006; +287 %, P = 0.0007 and; +286 %, P < 0.0001, respectively), and hyperglycemia (+43%, P=0.02). The kidney of some HFHS fed mice displayed mononuclear inflammatory cell infiltrate (40%), perivascular fibrosis (20%), and focal tubule mineralization (20%). Glomeruli hypertrophy was not detected. Unexpectedly, OPG, RANK, MMP-2 and MMP-9 expression was not altered in HFHS groups (Western blot analysis). In conclusion, the expression of RANKL/RANK/OPG system proteins and MMPs was not influenced by diet-induced obesity and diabetes in the kidney of male C57BL/6 mice, although some adverse histopathological remodeling is noticed in the renal tissue.

Histopathologic aspects of experimental cysticercosis and in situ cytokines profile in C57BL/6 mice

ABSTRACT Neurocysticercosis (NCC) is one of the parasitic infections that most affects the central nervous system. The knowledge regarding its immunopathogenesis and pathophysiology needs broadening. Taenia crassiceps cysticerci are used as the NCC experimental model. The aim of this work was to describe the general pathological processes and the in situ cytokine profile in C57BL/6 mice inoculated intracranially with viable T. crassiceps cysticerci. The histopathology analysis showed cysticerci in the extraparenchymal and intraventricular region, mononuclear inflammatory infiltration surrounding the parasite, microgliosis and meningitis. The analysis of the in situ immune profiles showed a predominance of the Th2 response. The IL-4 and IL-10 dosages were significantly increased in the infected group. The decrease in the INF-gamma dosage reflects the immunomodulation from the cysticerci. In conclusion, a T. crassiceps NCC infection in C57BL/6 mice triggers an inflammatory response, a predominance of Th2 type in situ profile, with mononuclear inflammatory cell infiltration, meningitis and microgliosis.

Deep Penetrating Nevus: A Review

Context.—Deep penetrating nevus is a distinctive melanocytic lesion that may simulate melanoma both clinically and histologically. Objective.—To review clinical and histologic features of deep penetrating nevi and discuss their differential diagnosis, especially regarding melanoma. Data Sources.—The literature on deep penetrating nevi is reviewed and supplemented by our experiences with deep penetrating nevi. Conclusions.—One or more disturbing histologic features may frequently be found in deep penetrating nevi, including asymmetry, plump but fairly regular nests of melanocytes in the dermis, cytologic atypia with some nuclear pleomorphism, a small to medium-sized eosinophilic nucleolus, absence of maturation, occasional presence of normal dermal mitoses, and a patchy mononuclear inflammatory cell infiltrate. Although unusual, such histologic features should not be regarded as a sign of malignancy in deep penetrating nevi.