The impact of adiposity on adipose tissue-resident lymphocyte activation in humans.

BACKGROUND/OBJECTIVES: The presence of T lymphocytes in human adipose tissue has only recently been demonstrated and relatively little is known of their potential relevance in the development of obesity-related diseases. We aimed to further characterise these cells and in particular to investigate how they interact with modestly increased levels of adiposity typical of common overweight and obesity. SUBJECTS/METHODS: Subcutaneous adipose tissue and fasting blood samples were obtained from healthy males aged 35-55 years with waist circumferences in lean (<94 cm), overweight (94-102 cm) and obese (>102 cm) categories. Adipose tissue-resident CD4+ and CD8+ T lymphocytes together with macrophages were identified by gene expression and flow cytometry. T lymphocytes were further characterised by their expression of activation markers CD25 and CD69. Adipose tissue inflammation was investigated using gene expression analysis and tissue culture. RESULTS: Participants reflected a range of adiposity from lean to class I obesity. Expression of CD4 (T-helper cells) and CD68 (macrophage), as well as FOXP3 RNA transcripts, was elevated in subcutaneous adipose tissue with increased levels of adiposity (P<0.001, P<0.001 and P=0.018, respectively). Flow cytometry revealed significant correlations between waist circumference and levels of CD25 and CD69 expression per cell on activated adipose tissue-resident CD4+ and CD8+ T lymphocytes (P-values ranging from 0.053 to <0.001). No such relationships were found with blood T lymphocytes. This increased T lymphocyte activation was related to increased expression and secretion of various pro- and anti-inflammatory cytokines from subcutaneous whole adipose tissue explants. CONCLUSIONS: This is the first study to demonstrate that even modest levels of overweight/obesity elicit modifications in adipose tissue immune function. Our results underscore the importance of T lymphocytes during adipose tissue expansion, and the presence of potential compensatory mechanisms that may work to counteract adipose tissue inflammation, possibly through an increased number of T-regulatory cells.

Increased thickness of pregnancy-associated melanoma.

The effects of pregnancy on the pathophysiology of melanoma remain unclear. Although a gender-specific advantage for women vs. men is seen for characteristics such as stage at presentation, site of primary tumour, and survival time, an adverse effect of pregnancy on melanoma development and progression has been reported. In a retrospective study, we investigated the tumour characteristics of women who developed pregnancy-associated melanoma, and compared them with melanomas arising in non-pregnant women of child-bearing age. The patient records of the Massachusetts General Hospital Pigmented Lesion Clinic were reviewed, and 465 women of reproductive age (16-45 years) who developed melanoma were identified. Of these, in 45 women (age 21-42 years) there was a close temporal relationship between diagnosis of the tumour and pregnancy. Clinical and histological characteristics of the primary tumours were recorded. Differences in tumour thickness, site and histological type were analysed. The mean thickness of pregnancy-associated melanomas was significantly greater than that of non-pregnancy-associated tumours (2.28 vs. 1.22 mm, respectively; P < 0.007). No differences in histological type (P = 0.64) or site (P = 0.74) of the primary tumours were found between the two patient groups. Not surprisingly, multivariate analysis revealed that tumour thickness was a statistically significant variable in determining prognosis (P = 0.001). An unexpected finding, on multivariate analysis, was a possible pregnancy-associated prognostic advantage (P = 0.08). Melanomas arising during pregnancy are thicker, but are not necessarily associated with a less favourable prognosis than tumours arising in non-pregnant women of child-bearing age.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen and progesterone receptor analysis in pregnancy-associated melanoma: absence of immunohistochemically detectable hormone receptors.

The role of estrogen in the initiation and progression of melanoma remains unclear. Some findings that suggest a hormonal role in melanoma initiation or progression include the following: (1) melanomas arising during pregnancy are thicker than those in nonpregnant women, (2) pregnant women with stage II (regional nodal metastases) melanoma have a worse prognosis than nonpregnant women of similar stage, and (3) melanoma is rare prior to puberty. Although biochemical assays have shown that estrogen-binding proteins are present in malignant melanoma, studies using a sensitive and more specific immunohistochemical technique have not found estrogen receptors (ERs) in melanoma. In our laboratory an immunohistochemical technique using monoclonal antibody H222 can detect ER in tumors with receptor levels lower than 9 fmol/mg protein and detects ER in a variety of tissues and species. In addition, monoclonal antibody KD68 is used to detect progesterone receptors immunohistochemically. We studied 14 cases of pregnancy-associated melanoma. None of our cases, ranging from melanoma in situ to metastatic melanoma, showed positive nuclear staining for ER, nor did any of these cases show positive immunohistochemical staining for progesterone receptor. Despite the wide tissue and species distribution of ER detected by the monoclonal antibody H222, this immunohistochemical technique does not appear to be useful in the study of possible hormonal effects on the progression of malignant melanoma. The estrogen-binding proteins in melanoma detected by biochemical techniques in previous studies probably are distinct from the well-defined human ER.

Systemic lupus erythematosus presenting as post-partum chorea.

A case of systemic lupus erythematosus (SLE) is reported in which chorea was the dominant clinical feature, and which presented following a spontaneous mid-trimester abortion. The diagnosis, natural history and management of this uncommon manifestation of CNS lupus is discussed, as well as the influence of pregnancy on disease activity in SLE.

The neuropsychiatric disorder in systemic lupus erythematosus: evidence for both vascular and immune mechanisms.

As part of a prospective survey of systemic lupus erythematosus (SLE) a detailed collaborative study of the clinical, psychiatric, and laboratory features in 15 patients with nonfocal neuropsychiatric disease has been undertaken. In addition to conventional clinical and psychometric evaluation, electroencephalograph, and cerebrospinal fluid analysis, the study included the assessment of cerebral blood flow with oxygen-15 brain scans and serological testing for the presence of antineuronal and lymphocytotoxic antibodies. Of the 15 patients 12 had psychiatric manifestations, while 13 had various neurological abnormalities. All except 2 episodes of cerebral disease were transient. Striking abnormalities in cerebral blood flow and metabolism were seen in 12 patients, even in the presence of subtle clinical features. Sequential scans showed that improvement in clinical features was accompanied by a reversal of scan abnormalities. All sera contained brain-reactive antibody, either antineuronal IgG antibody (13) or lymphocytotoxic IgM antibody (12) or both (10), though there was an inconsistent association between clinical features and antibody titre. It is suggested that transient disturbances of cerebral vascular function in SLE might allow brain-reactive antibodies from the circulation access to cerebral tissue. In this way the nature of the neuropsychiatric abnormalities would depend on both vascular and immunopathogenic mechanisms.

Sacro-iliac joint scanning with technetium-99 diphosphonate.

Quantitative sacro-iliac (SI) joint scanning with methylene diphosphonate labelled with technetium-99 (99TcMDP) was performed in 25 control patients, in 16 patients with definite ankylosing spondylitis, in 23 patients with mechanical low back pain, and in 12 patients with seronegative arthritis. The mean radio-isotope index in the control group was 1.2 +/- 0.15. The highest value was 1.5. Values in excess of 1.5 were seen in patients with clinically active ankylosing spondylitis but not those with inactive disease. Three of the 12 seronegative arthritis patients (without clinical or radiological evidence of sacro-iliitis) had elevated values: all of these were positive for HL-A B27. An important finding was that six of the 23 patients with mechanical or non-specific low back pain had values above 1.5, unassociated with B27. These data emphasize the need for caution in the interpretation of abnormal sacro-iliac scans. Radio-isotope bone scanning can provide a qualitative and quantitative assessment of inflammatory activity in joints with minimal radiation exposure. Various authors have shown its value in providing early evidence of sacro-iliitis (Russell et al., 1975; Namey et al., 1977). In this study, methylene diphosphonate labelled with technetium-99 (99TcMMDP) has been used to produce quantitative sacro-iliac scans in order to evaluate sacro-iliac disease in four groups of patients presenting with or without low back pain.

Oxygen-15 brain scanning for detection of cerebral involvement in systemic lupus erythematosus.

In 47 patients with systemic lupus erythematosus seen during fifty-one clinical episodes, oxygen-15, a short-lived gamma-emitting isotope, has been employed in a scannng technique to study cerebral oxygen utilisation and blood-flow. Abnormalities in regional distribution of oxygen utilisation and blood-flow were seen in twenty-three out of twenty-four instances of definite central-nervous-system disease, in fourteen out of fifteen instances of suspected C.N.S. lupus, and in ten out of twelve instances in which C.N.S. disease was not clinically apparent. The technique reflected remissions and relapses. It may prove valuable in diagnosis of subclinical cerebral disease, in monitoring of responses to therapy, and in study of the pathophysiology of cerebral lupus.

Oral contraceptive therapy and systemic lupus erythematosus.

The relationship between oral contraceptive therapy and systemic lupus erythematosus is not well defined. It has been reported that oral contraceptives may induce lupus: they may also exacerbate pre-existing disease. This report concerns a young woman in whom systemic lupus erythematosus developed three weeks after the commencement of oral contraceptive therapy, but who was shown to have had a chronic biological false positive serological test for syphilis for eight months prior to this. The significance of false positive serological tests for syphilis and the effect of female sex hormones on disease activity in systemic lupus erythematosus is discussed.

PIP: Oral contraceptive therapy has been reported to induce systemic lupus erythematosus (SLE) and rheumatic complaints with normal and abnormal serology. A case report is presented of a 23-year-old female in whom SLE developed 3 weeks after initiation of oral contraceptive (ethinyl estradiol 50 mg and norethisterone acetate 1 mg) usage, but who had experienced a chronic biological false positive (BFP) serological test for syphilis for 8 months prior to this. This implies that she had either a lupus diathesis or subclinical SLE which was unmasked by pill therapy rather than a de novo disease caused by this agent. A study of 134 patients with chronic BFP reactions found that 10 developed SLE, 4 developed discoid LE, and 6 developed a multiple sclerosis-like neuropathy probably due to SLE. BFP reaction is found in 10-20% of SLE patients. Other studies have found oral contraceptive therapy to exacerbate existing SLE and to induce serological markers (LE cells, antinuclear antibody, rheumatoid factor). In cases where SLE was exacerbated, the estrogen involved was either mestranol (0.5-1 mg) or ethinyloestradiol (0.5 mg). However, studies of women without symptoms have failed to show a significant association between oral contraceptive therapy, SLE serological markers, and rheumatic complaints. There is considerable evidence that female sex hormones play a role in determining SLE disease activity. There is a constant male:female ratio of 1:9, and the tendency to disease activity increases premenstrually, in pregnancy, and in the postpartum period.