Myoid and epithelial cell differentiation in myasthenic thymuses.

This study demonstrates that the stromal thymus elements of postcapillary venules are the source of desmin-positive mesenchyme from which both myoid and epithelial cells arise. The double staining revealed various degrees of desmin and keratin positivity in the same kind of cells in the medulla as well as in Hassall's corpuscles. Hassall's corpuscles seem to arise from several kinds of cells of which one appears to be monocytogenic and expressed S100 protein.     

Acetylcholine receptor alpha-subunit isoforms are differentially expressed in thymuses from myasthenic patients.

A central role of the thymus in autosensitization to the acetylcholine receptor has been proposed to explain the immunopathogenetic processes in myasthenia gravis (MG). Two isoforms of the alpha-subunit of the acetylcholine receptor are known; they differ by a 25-amino-acid insertion coded by the P3A exon. We investigated the expression of the P3A exon by RNA polymerase chain reaction in fetal and adult human myoblasts and TE671 cells; both isoforms were expressed. Muscle biopsies from patients with MG, Duchenne muscular dystrophy, and polymyositis were also studied and it was again found that both isoforms were expressed, indicating that the P3A exon is not associated with autoimmune, degenerative, and inflammatory muscle diseases. When P3A expression was studied in thymus samples from normal subjects and from thymectomized MG patients, the P3A+ subunit was absent in 75% of patients with involuted thymus and in all patients with thymomas but was present in normal thymuses and in patients with hyperplasia. Differential expression of the alpha-subunit isoforms of the acetylcholine receptor within the thymus may play a role in the immune pathogenesis of MG.     

Histioeosinophilic granulomas in the thymuses of 29 myasthenic patients: A complication of pneumomediastinum

Nodular aggregates of histiocytes and eosinophils, described as "histioeosinophilic granulomas," were found in the capsules and septa of 29 of 63 nonneoplastic thymuses (45 per cent) removed from patients with myasthenia gravis. The configurations and cytologic appearances of the lesions resembled those of eosinophilic granuloma, but a combination of morphologic, immunohistochemical, and ultrastructural studies failed to demonstrate a Langerhans' cell component in these lesions. This heretofore unrecorded thymic lesion might represent the thymic counterpart of a pleural process that has been described as "reactive eosinophilic pleuritis" in patients with spontaneous pneumothorax and was probably induced by diagnostic pneumomediastinum performed prior to thymectomy. It is of interest, however, that the presence of these granulomas was correlated with an increased probability of remission of myasthenic symptoms following thymectomy.     

Immunopathological study on palmar aponeurosis in Dupuytren's disease

The authors examined the immunological and immunohistochemical alterations of palmar aponeurosis in Dupuytren's contracture. In the IgG-content no difference were found between the intact and diseased aponeurosis. The mean of IgA content was 2 fold, the IgM content 3 fold higher in Dupuytren's aponeurosis than in normal ones. The immunoglobulin containing cells localised around the Dupuytren's nodules and in fibrotic, but not nodular parts of aponeurosis. Extracellular immunoglobulin deposits were not found.     

Immunopathological study of spleen during Japanese encephalitis virus infection in mice

Following intraperitoneal inoculation, Japanese encephalitis virus replicated in peritoneal macrophages, appeared on day 3 in the splenic macrophages of the perifollicular region and later in cells of the periarteriolar lymphoid sheath (PALS) as shown by indirect immunofluorescence. Productive JEV infection was observed both in macrophages and T-cells. Morphological study of spleen during JEV infection revealed proliferative changes, with increased number of macrophages from day 3 p.i. in the perifollicular region followed by accumulation of polymorphonuclear leucocytes which reached a maximum on day 9 p.i. The T dependent areas were considerably enlarged by day 9 and gradually reduced in size by week 3. At later periods germinal centres appeared in the T independent area and were prominent by day 15. The cells containing virus antigen disappeared with the appearance of germinal centres, thus indicating the role of the latter also in virus clearance.     

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

PurposeKabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype–phenotype correlations in KS individuals from a registry.MethodsData were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis.ResultsOverall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027).ConclusionThe high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.     

Immunopathological study of spleen during Japanese encephalitis virus infection in mice.

Following intraperitoneal inoculation, Japanese encephalitis virus replicated in peritoneal macrophages, appeared on day 3 in the splenic macrophages of the perifollicular region and later in cells of the periarteriolar lymphoid sheath (PALS) as shown by indirect immunofluorescence. Productive JEV infection was observed both in macrophages and T-cells. Morphological study of spleen during JEV infection revealed proliferative changes, with increased number of macrophages from day 3 p.i. in the perifollicular region followed by accumulation of polymorphonuclear leucocytes which reached a maximum on day 9 p.i. The T dependent areas were considerably enlarged by day 9 and gradually reduced in size by week 3. At later periods germinal centres appeared in the T independent area and were prominent by day 15. The cells containing virus antigen disappeared with the appearance of germinal centres, thus indicating the role of the latter also in virus clearance.     

Antibodies to the acetylcholine receptor in myasthenic dogs.

Antibodies to the AChR and anti-striational antibodies have been detected in dogs suffering from myasthenia gravis. The detection of these antibodies adds to the known similarities between the human and canine disease. This animal model will facilitate investigation of agents involved in the induction of spontaneous myasthenia gravis.     

Immunopathological changes in rheumatoid arthritis and other joint diseases.

A comparative study of the distribution of immunoglobulins G, M, and A and C3 in the synovium and inside synovial fluid leucocytes and of the relative levels of IgG, IgM, AND C3 in paired samples of serum and synovial fluid from both seropositive and seronegative patients with rheumatoid arthritis and other types of non-infective synovitis shows that although there is no distinctive immunopathological feature of rheumatoid arthritis, the incidence of immune complexes containing IgG and IgM with and without detectable C3 in the affected synovium or inside synovial fluid granulocytes is higher in rheumatoid arthritis and especially so in seropositive cases. The mean level of C3 in synovial fluid from patients with rheumatoid arthritis is lower than that from the group without rheumatoid arthritis. In contrast to previous reports, extracellular clumps of IgA could be detected in the affected synovium of a number of affected patients. Aggretated human IgG could be bound by some of the synovial biopsies and synovial fluid leucocytes from both seropositive and seronegative rheumatoid arthritis patients. Antinuclear factor and rheumatoid factor could be detected in the synovial fluid but not in the serum of several patients suggesting either selective sequestration or local synthesis of antinuclear and rheumatoid factors in the affected joints.     

Traffic of peripheral B and T lymphocytes to hyperplastic, preneoplastic thymuses of AKR mice.

AKR mice develop hyperplasia of the thymus before the development of retrovirus-associated lymphoma at that site. This hyperplasia, first detectable in AKR/J mice by 4 weeks of age and in AKR/C mice by 4 to 5 months of age, is characterized by an enlarged thymic medulla that contains T and B lymphocytes. In contrast to the general population of thymocytes, most of these T and B lymphocytes have a mature immunophenotype that includes expression of high levels of the MEL-14-defined (gp90) 'homing receptor' for peripheral lymph node high endothelial venules. In vivo homing studies reveal a marked increase in traffic of peripheral lymphocytes (T more than B) to the hyperplastic thymuses of old AKR mice as compared to histologically normal thymuses of age-matched BALB/c and C57BL/Ka mice or young AKR mice. These changes correlate chronologically with changes in retrovirus antigen expression in AKR thymuses and suggest a role for the traffic of lymphocytes from the periphery to the thymus in response to local antigenic stimulation in the pathogenesis of thymic hyperplasia in AKR mice.     

Estimated contribution of hemoglobin and myoglobin to near infrared spectroscopy

We calculated the light absorbing potential (LAP) of hemoglobin (Hb) and myoglobin (Mb) in mammalian skeletal muscle at rest based on analysis of published chemical and morphometric data (Part 1), interpreted changes in total[Hb + Mb] from NIRS during exercise (Part 2), and estimated the potential contribution of Hb and Mb to changes in NIRS from rest to exercise (Part 3). Part 1: [Hb] in skeletal muscle was estimated from microvascular volume, systemic blood [Hb], and microvascular hematocrit and saturation at rest and during exercise. Part 2: Changes in total[Hb + Mb] (as t[Hb + Mb]) during cycling or knee extension exercise were interpreted using the results of Part 1. Part 3: Using estimates of mean microvascular PO₂, Hb and Mb contribution at peak exercise was estimated. Across several species, [Mb] contributed ∼50–70% of the total LAP to NIRS at rest in skeletal muscle. With exercise, increases in t[Hb + Mb] of up to 30% could be entirely explained by the predicted increase in microvascular hematocrit with exercise. Finally, Mb was estimated to contribute ∼70% of the changes in NIRS from rest to peak exercise.     

Distribution of anti-keratins and anti-thymostimulin antibodies in normal and in Down's syndrome human thymuses.

The localization of three monoclonal (A,B,C) anti-cytokeratin antibodies and of an anti-thymostimulin antibody were studied in normal children's thymuses, aged from 2 months to 10 1/2 years and in Down's children thymuses, aged from 5 months to 6 1/2 years. Two anti-cytokeratins were positive in the thymus: the anti-B was found in the epithelial cells of all thymic zones, the anti-C only in the external cells of Hassall's corpuscles. The distribution and the intensity of immuno-reactions were the same in normal and in Down's thymuses. The distribution of anti-thymostimulin was superimposed to the distribution of anti-cytokeratin B and was similar in normal and in the youngest Down's thymuses, whereas in the 6 1/2 years-old Down's thymuses there was a loss of anti-TS reaction in the subcapsular zone. A relationship between the reduction of anti-thymostimulin immuno-reaction and the beginning of an eventual loss of T-lymphocyte differentiation was supposed.     

Antibody response to the C-terminal peptide sequence in beef myoglobin

The nature of the surface determinants on the beef myoglobin molecule which direct the distinctive antibody response of sheep, have been further defined. Antisera raised to beef myoglobin in sheep, rabbits and mice have been compared for their ability to recognize the synthetic C-terminal beef myoglobin peptide (140–153), which contains four of the six amino acid substititutions between sheep and beef myoglobins. The antibodies raised in rabbits, directed to the entire surface of beef myoglobin, contain only a minor population directed to the C-terminal sequence: in mice, even fewer antibodies are specific for this sequence. In sheep, however, antibodies to beef myoglobin appear to be directed almost exclusively to topographic domains which include the (140–153) sequence. This specificity is most apparent in “early” antisera in which all antibodies display equal avidity for “native” beef myoglobin and the peptide; further immunization produces antibodies which recognize a larger overlapping set of domains and only 20% of these antibodies have effective avidity for the (140–153) peptide. The antibodies to beef myoglobin raised in sheep comprise two discrete populations. One (“common”) population is directed to regions of similarity between the beef and sheep myoglobin molecules, in which the region represented by the C-terminal peptide of beef myoglobin is less important in defining the antibody-binding site and/or affinity, while still being directly involved in the topographic determinant. The other (“non-common”) appears to be directed almost exclusively to the C-terminal sequence (140–153) of beef myoglobin. The findings are discussed in relation to our previous findings on the effect of the host species on the nature of the antibody response and in relation to views on the possibility of direct vs indirect effects of evolutionary amino acid substitution on immuno-cross-reactivity among homologous proteins.     

Arterial reconstructive surgery and myoglobin

To assess the diagnostic value of myoglobin between elective surgery and acute arterial occlusion, serum and urine myoglobin (S-Mb, U-Mb) levels were measured before and for 7 consecutive days following arterial reconstructive surgery in 7 patients with abdominal aortic aneurysm or arteriosclerosis obliterans (elective surgery group), and in 20 patients with acute arterial occlusion due to embolism or thrombosis. They were divided into three groups based on symptoms and other features: mild, moderate, and severe groups. S-Mb and U-Mb levels were normal before surgery with a maximum of 389 ng/ml and 1,670 ng/ml after surgery in the elective surgery group, and 489 ng/ml and 11.7 ng/ml before surgery with a maximum of 703 ng/ml and 294 ng/ml after surgery in the mild cases. These two groups showed no complications after surgery. In the moderate group, high values of 2,420 ng/ml and 25,300 ng/ml were noted before surgery, and these values were elevated to 14,900 ng/ml and 175,000 ng/ml after surgery with complications of acute renal failure or peripheral nerve paresis. In the severe group, the values were 9,440 ng/ml and 260,000 ng/ml before surgery, and 160,000 ng/ml and 1,300,000 ng/ml after surgery, the elevation being associated with the severe clinical complication, myonephropathic metabolic syndrome (MNMS). All patients in this group died of MNMS. S-Mb and U-Mb levels before surgery proved useful for predicting the prognosis of patients with acute arterial occlusion. The findings obtained in our canine studies on the mechanism and treatment of MNMS suggest that alpha-tocopherol, a free radical scavenger, may be effective for treating dreadful complications such as MNMS.     

Immunopathological changes in the skin following recombinant interleukin-2 treatment

The systemic administration of the cytokine recombinant interleukin-2 (rIL-2) is associated with a number of toxic effects, including dermatological complications. The clinical, histological, and immunopathological changes occurring in the skin of six patients receiving rIL-2 for metastatic colorectal carcinoma have been studied. All of the patients developed a diffuse erythema shortly after initiation of the treatment. In one patient, generalized erythroderma and photosensitivity developed. The initial biopsy revealed patchy spongiosis, focal exocytosis, and focal basal layer damage with a perivascular chronic inflammatory cell infiltrate. With further treatment there was progressive thickening of the epidermis, Immunohistochemistry revealed changes in the expression of CD1, CD3, CD4, and CD25, particularly on perivascular cells. Additionally, there was an increase in the expression of intercellular adhesion molecule-1 (ICAM-1) on keratinocytes in the basal and mid-layers of the epidermis, endothelial cells, and perivascular cells. It is hypothesized that the expression of ICAM-1 by the epidermal keratinocytes may be the important event in initiating the cutaneous manifestations associated with rIL-2 administration.