Hajime Kodama

Follicular Mucinosis: Response to Indomethacin

A patient with follicular mucinosis was treated topically and orally with indomethacin. He had generalized plaques and grouped follicular papules but no signs of cutaneous lymphoma. The skin lesions responded favorably to topical application. Oral administration produced a dramatic improvement. No recurrence has been seen for 5 years after stopping the treatment.

Cutaneous mucinosis associated with SLE--a case provoked by PUVA.

A patient with SLE which was complicated by a characteristic cutaneous mucinosis is reported. The skin lesions were composed of intradermal soft nodules, purple‐red plaques, and alopecia of the scalp. Acid mucopolysaccharides accumulated in each lesion. PUVA provoked an infiltrated skin lesion in which acid mucopolysacchraides were deposited in the dermis. Deposition of immunoglobulins and complements were also observed at the dermo‐epidermal junction and on the vascular walls. Some immunological processes which may stimulate the synthesis of acid mucopolysaccharides in the dermis were suggested.

Persistence of foam cells in rabbit xanthoma after normalization of serum cholesterol level

SummaryXanthoma was produced in diet-induced hypercholesterolemic rabbits by intradermal dextran sulfate injections. The serum cholesterol level returned to the normal range at about 10 weeks after ending the cholesterol diet. Gross observations after cessation of the cholesterol diet revealed a decrease in xanthomatous infiltrations. However, the dense foam cell infiltrations and cholesterol accumulations showed no signs of regression at even 9 months after ending the cholesterol diet. Signs of foam cell migration into the blood stream were not observed. The peristence of the xanthoma may be due to a lack of acceptors, such as high-density lipoproteins, that remove the cholesterol from the foam cells. During our 9-month observation period, some foam cells were degenerated and a few were fused with each other to transform into Touton-type giant cells. Nonfoamy histiocytes were infiltrated around these degenerating foam cells. The histiocytes may have transformed into foam cells by incorporating the lipids of the degenerated foam cells.

AN EXPERIMENTAL MODEL OF XANTHOMA BY INTRADERMAL DEXTRAN SULFATE INJECTION

Large molecular weight sodium dextran sulfate (SDS) injection into the dermis of both normolipemic rabbits and hypercholesterolemic rabbits induced infiltration of histiocytes and foam cells. Sudan III staining showed that the histiocytes and foam cells of hypercholesterolemic rabbits accumulated lipids similarly to xanthoma foam cells. The accumulated lipids increased as the injection was repeated at the same site. However, the lipid accumulation was minimal in the histiocytes of normolipemic rabbits. As determined by quantitative analysis of lipid composition in the lesions of hypercholesterolemic rabbits, cholesterol esters remarkably increased concomitantly with injection frequency. Free cholesterol accumulation was less pronounced than cholesterol ester. In normolipemic rabbit dermis, accumulation of free cholesterol was insignificant and cholesterol esters did not accumulate progressively with repeated SDS injections. Apparently the foam cells of hypercholesterolemic rabbits actively incorporated serum low density lipoproteins (LDL) and cholesterol was esterified in the foam cells. On the other hand, LDL were minimally incorporated into histiocytes in the normolipemic state. The intradermal SDS injection is a beneficial experimental model for further investigations on the mechanisms of lipid accumulation and the intracytoplasmic lipid metabolism of xanthoma foam cells.

IMMUNOHISTOCHEMICAL STUDY OF HUMAN XANTHOMA

Specimens of human tuberous xanthomas obtained from two hyper‐β‐lipoproteinemic patients were prepared with HE and Sudan III stain and by direct immunofluorescence with fluorescein isothiocyanate labeled antihuman β‐lipoprotein rabbit serum. In some histiocytes and foam cells in early stages, lipids were stained in granular patterns and specific fluorescence was observed. In some foam cell nests, specific fluorescence was weak or absent, and orange‐colored lipid autofluorescence was present. The foam cells in such nests were probably late foam cells and corresponded to the large cytoplasmic foam cells stained densely and amorphously for lipids. It was concluded that at early stages of xanthoma formation, serum lipoproteins were incorporated into dermal histiocytes and early foam cells. The apoproteins of the incorporated lipoproteins were probably degraded and lipid residues accumulated in the cells. Specimens of tuberous xanthoma covered by plane xanthoma showed lipids and bright specific fluorescence at the basement membrane zone. A faint fluorescence was observed in the upper dermis and even in parts of the epidermal intercellular spaces.

Process of foam cell formation in diet-induced hypercholesterolemic rabbit and the Watanabe heritable hyperlipidemic rabbit.

Xanthoma was induced by intradermal dextran sulfate (DS) injections into diet‐induced hypercholesterolemic rabbits (HCR) and a Watanabe heritable hyperlipidemic (WHHL) rabbit. The number of infiltrating foam cells and the accumulation of cholesteryl esters, especially cholesteryl oleate, were more remarkable in a HCR with extremely high serum cholesterol level (1,176 mg/100 ml) than in the WHHL rabbit (serum cholesterol level of 327 mg/100 ml), but the number of infiltrating foam cells and the accumulation of cholesteryl esters were similar in a HCR with a serum cholesterol level of about 300 mg/100 ml and the WHHL rabbit. Apparently, the infiltration of foam cells and their accumulations of cholesteryl esters were correlated with serum total cholesterol level. Cholesterol esterification was stimulated and cholesterol synthesis was suppressed in the histiocyte infiltrating dermis incubated with very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) from either the HCR or WHHL rabbit. But supplements of the LDL from normolipemic rabbits (NLR) did not strongly stimulate cholesterol esterification and scarcely suppressed cholesterol synthesis. This suggests that the lipoproteins of the HCR and WHHL rabbit are more easily taken up by dermal histiocytes than the LDL of the NLR. Among the separate lipoprotein classes of the two distinct types of hypercholesterolemic rabbits, there were no significant differences in cholesterol esterification stimulation or cholesterol synthesis suppression.

XANTHOMA FORMATION BY HUMAN β‐LIPOPROTEIN IMMUNE COMPLEXES IN RABBIT BLOOD STREAM

Two untreated rabbits and two rabbits sensitized with human β‐lipoproteins were intravenously injected with human β‐lipoproteins (20 mg as proteins) once a day for 18 days. One of the sensitized rabbits revealed three xanthomas along a yellow tendon of the left leg. Elevation of serum cholesterol level by the repeated injections was slight. Histologically, the xanthomas showed many foam cell nests around the vessels. Numerous polymorphonuclear cells and histiocytes were observed in the central area of these nests. Mature foam cells crowded the peripheral zone. In the intermediate zone, immature foam cells appeared. Immunohistochemical and lipid histochemical studies indicated the incorporation of human β‐lipoproteins into the histiocytes and immature foam cells. In the mature foam cells, however, apoproteins of human β‐lipoproteins had been degraded. The xanthomas apparently developed from the incorporation of extravasated human β‐lipoprotein immune complexes into dermal histiocytes. It is conceivable that human β‐lipoproteins were incorporated more easily in the aggregated immune complex form than in their natural form. Another possibility is that human β‐lipoproteins were more readily incorporated when they were rendered polycationic by complexing with immunoglobulins.

XANTHOMA-INDUCING β-LIPOPROTEIN IMMUNE COMPLEXES

Untreated rabbits and rabbits sensitized with human β‐lipoproteins were intracutaneously injected with either human or rabbit β‐lipoproteins (2 mg as protein). Forty‐eight hours later, at the human β‐lipoprotein injection site, dense cell infiltrations stood out sharply demarcated from the surrounding region. The infiltrating cells were composed of polymorphonuclear cells, nuclear dust and histiocytes. Foam cell nests were observed in sensitized rabbit dermis one week after human β‐lipoprotein injection. Direct immunofluorescence employing fluorescein isothiocyanate labeled antihuman β‐lipoprotein antiserum showed that the injected human β‐lipoproteins were incorporated into the infiltrating cells of sensitized rabbit dermis up to 48 hours after injection. Specific fluorescence was greatly reduced but lipid autofluorescence remained in mature foam cells. During the 3‐week examination period, no trace of foam cell nests was found at the site of human β‐lipoprotein injection on non‐sensitized rabbits. Intracutaneous rabbit β‐lipoprotein injection revealed no histiocytic infiltrations in either sensitized or non‐sensitized rabbits. These findings indicated that intracutaneously injected human β‐lipoporteins were incorporated into rabbit dermal histiocytes more easily in aggregated immune complex form than in their natural state. These histiocytes were easily transformed to foam cells. Apoproteins of the incorporated lipoproteins were degraded, and lipid residues accumulated in mature foam cells.

Acid Cholesterol Esterase Activity in the Foam Cells Isolated from Rabbit Experimental Xanthoma Tissues

Acid cholesterol esterase (ACE) activity was assayed in the 10,000×g pellet from infiltrating cells isolated from experimental rabbit xanthoma tissues. Skin specimens were obtained from sites of intradermal dextran sulfate injections on a normolipemic rabbit (NLR) and a diet‐induced hypercholesterolemic rabbit (HCR). Most infiltrating cells were histiocytes or foam cells. Histiocytes from the NLR did not accumulate cholesteryl esters after the injections. Accumulation of cholesteryl esters in the xanthoma tissues of the HCR increased after repeating the injections at the same site. The ACE activity was greater in the cholesteryl ester‐accumulated foam cells than in histiocytes. The enzyme activity in the foam cells decreased during the developmental course of cholesteryl ester accumulation. These findings indicate that lysosomal ACE is activated and hydrolyzes the internalized cholesteryl esters of serum lipoprotein origin in the histiocytes which are transforming into foam cells. However, the enzyme activity decreases when too much of the cholesteryl esters has accumulated in the foam cells.