The function of the thymus and its impact on modern medicine

The lymphoid system is intimately involved in immunological processes. The small lymphocyte that circulates through blood into lymphoid tissues, then through the lymph and back to the blood through the thoracic duct, is able to initiate immune responses after appropriate stimulation by antigen. However, the lymphocytes found in the thymus are deficient in this ability despite the fact that the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological faculty. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and in other lymphoid tissues. They become “educated” in the thymus to recognize a great diversity of peptide antigens bound to the body’s own marker antigen, the major histocompatibility complex, but they are purged if they strongly react against their own self-components. Lymphocytes differentiate to become various T cell subsets and then exit through the bloodstream to populate certain areas of the lymphoid system as peripheral T lymphocytes with distinct markers and immune functions.

Orofacial skin inflammation increases the number of macrophages in the maxillary subregion of the rat trigeminal ganglion in a corticosteroid-reversible manner

Inflammation of the cutaneous orofacial tissue can lead to a prolonged alteration of neuronal and nonneuronal cellular functions in trigeminal nociceptive pathways. In this study, we investigated the effects of experimentally induced skin inflammation by dithranol (anthralin) on macrophage activation in the rat trigeminal ganglion. Tissue localization and protein expression levels of ionized calcium-binding adaptor molecule 1 (Iba1), a macrophage/microglia-specific marker, and proliferation/mitotic marker antigen identified by the monoclonal antibody Ki67 (Ki67), were quantitatively analyzed using immunohistochemistry and western blots in control, dithranol-treated, dithranol- and corticosteroid-treated, and corticosteroid-treated trigeminal ganglia. Chronic orofacial dithranol treatment elicited a strong pro-inflammatory effect in the ipsilateral trigeminal ganglion. Indeed, daily dithranol treatment of the orofacial skin for 3–5 days increased the number of macrophages and Iba1 protein expression in the maxillary subregion of the ipsilateral ganglion. In the affected ganglia, none of the Iba1-positive cells expressed Ki67. This absence of mitotically active cells suggested that the accumulation of macrophages in the ganglion was not the result of resident microglia proliferation but rather the extravasation of hematogenous monocytes from the periphery. Subsequently, when a 5-day-long anti-inflammatory corticosteroid therapy was employed on the previously dithranol-treated orofacial skin, Iba1 immunoreactivity was substantially reduced in the ipsilateral ganglion. Collectively, our findings indicate that both peripheral inflammation and subsequent anti-inflammatory therapy affect macrophage activity and thus interfere with the functioning of the affected sensory ganglion neurons.

Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.

PAX-2 Is a Helpful Marker for Diagnosing Metastatic Renal Cell Carcinoma: Comparison With the Renal Cell Carcinoma Marker Antigen and Kidney-Specific Cadherin

Context.—The diagnosis of metastatic renal cell carcinoma (RCC) remains problematic. Objective.—To evaluate the role of PAX-2, a renal tubular cell transcription factor, in the diagnosis of metastatic RCC. PAX-2 expression in metastatic RCC was compared with that of the renal cell carcinoma marker antigen (RCCM) and kidney-specific cadherin (KSC), which are 2 known markers for RCC. Design.—Immunostaining for PAX-2, RCCM, and KSC was performed on consecutive tissue sections of 95 metastatic RCCs (77 clear cell, 8 papillary, 5 sarcomatoid, and 5 collecting duct) and 183 metastatic tumors other than RCC. Results.—For PAX-2, positive immunoreactivity was detected in 77% clear cell, 75% papillary, 100% collecting duct, and 0% sarcomatoid metastatic RCCs. For RCCM, positive immunoreactivity was detected in 49% clear cell, 75% papillary, 0% collecting duct, and 0% sarcomatoid metastatic RCCs. For KSC, only 2 metastatic clear cell RCCs (3%) were positive. In combination, all markers were positive in 0% of cases; all markers were negative in 23% of cases (17 clear cell, 1 papillary, and for all 5 sarcomatoid); and at least 1 marker was positive in 76% of cases (PAX-2 only in 28% of cases [21 clear cell, 1 papillary, and 5 collecting duct] and RCCM only in 3% of cases [2 clear, 1 papillary]). Of 183 metastatic tumors other than RCC, 14 were positive for PAX-2 (nodal metastasis of carcinoma of colon [1], breast [1], endometrium [1], and ovary [1]; and omental metastasis of carcinoma of uterus or ovary [10]). Conclusions.—PAX-2 is a sensitive and specific marker for metastatic RCC. The diagnostic yield would be marginally increased by adding RCCM, but not KSC, as an immunomarker.

Characteristics of carotid body chemosensitivity in NADPH oxidase-deficient mice

Various heme-containing proteins have been proposed as primary molecular O2 sensors for hypoxia-sensitive type I cells in the mammalian carotid body. One set of data in particular supports the involvement of a cytochrome b NADPH oxidase that is commonly found in neutrophils. Subunits of this enzyme have been immunocytochemically localized in type I cells, and diphenyleneiodonium, an inhibitor of the oxidase, increases carotid body chemoreceptor activity. The present study evaluated immunocytochemical and functional properties of carotid bodies from normal mice and from mice with a disrupted gp91 phagocytic oxidase (gp91 phox ) DNA sequence gene knockout (KO), a gene that codes for a subunit of the neutrophilic form of NADPH oxidase. Immunostaining for tyrosine hydroxylase, a signature marker antigen for type I cells, was found in groups or lobules of cells displaying morphological features typical of the O2-sensitive cells in other species, and the incidence of tyrosine hydroxylase-immunopositive cells was similar in carotid bodies from both strains of mice. Studies of whole cell K+currents also revealed identical current-voltage relationships and current depression by hypoxia in type I cells dissociated from normal vs. KO animals. Likewise, hypoxia-evoked increases in intracellular Ca2+ concentration were not significantly different for normal and KO type I cells. The whole organ response to hypoxia was evaluated in recordings of carotid sinus nerve activity in vitro. In these experiments, responses elicited by hypoxia and by the classic chemoreceptor stimulant nicotine were also indistinguishable in normal vs. KO preparations. Our data demonstrate that carotid body function remains intact after sequence disruption of the gp91 phox gene. These findings are not in accord with the hypothesis that the phagocytic form of NADPH oxidase acts as a primary O2 sensor in arterial chemoreception.