The antigenic systems of the major histocompatibility complex can be subdivided into those which are serologically detectable and those which are detected in tests with mixed lymphocytes. The two systems have different roles in the activation of separate populations of T lymphocytes.

Differential function of major histocompatibility complex antigens in T-lymphocyte activation.

Our interest in immunogenetics started with the quite fortuitous finding that cytotoxic thymus-derived lymphocytes (T cells) from mice infected acutely with lymphocytic choriomeningitis virus (LCMV) interact only with H-2 compatible virus-infected target cells (Doherty & Zinkemagel 1974, Zinkemagel & Doherty 1974b). The idea underlying our original experiment was that, because acute LCM is apparently a T cell-mediated immunopathol ogical process, variations in susceptibility to LCM disease may be due to genetically determined differences in T cell responsiveness (Tosolini & Mims 1971, Doherty & Zinkemagel 1974, McDevitt et al. 1974). We found, however, that there was an all-or-none effect: virus-infected L-929 fibroblasts (L cells, H-2'') were lysed only by H-Z\" compatible virusimmune T cells. The significance of this result was immediately recognized, not least because the paper of Katz et al. (1973) on H-2 restriction of T cell helper activity had recently appeared. The immediate reaction was

Specificity of Virus‐Immune Effector T Cells for H‐2K or H‐2D Compatible Interactions: Implications for H‐Antigen Diversity

Publisher Summary This chapter discusses the use of H-2 mutations to study functions of the murine major histocompatibility complex. A single H-2 locus can control a variety of immunologic phenomena, and strong MLC reactions can occur to H-2K and D antigens as well as to I region antigens. Histogenetically and serologically detectable antigens are of comparable complexity and small changes in the H-2 molecule—a single amino acid substitution—can have drastic effects on phenotype. The chapter describes methods of detection and analysis of histocompatibility mutations in general and H-2 mutations in particular. The knowledge of H-2 mutations is related to the perennial problem of polymorphism. The individual immune functions are discussed, and data are presented on the way mutations change these functions. In the allograft reaction—the reaction on which the detection of H-2 mutations is based—antigens carried by the transplant are recognized by specific receptors on T lymphocytes. In vitro studies indicate that the H-2 antigens recognized by T cells are complex in the sense that different T cells presumably recognize different portions of the H-2 molecule.

H-2 mutations: their genetics and effect on immune functions.

INTRODUCTION .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . .. . . . . . . . . . . . . . . .. . . . . ...... . . . . . . . . . . . ...... . . . . . . . . . . . . . . . 241 General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . ..... . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . ..... . 241 Background on the Muri,.Major Histocompatibility Complex (H-2) . . . . . . . . . . .. . .... .. . 242 Background on the !;-� Mutant Strains. ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Background on the Biochemistry of the H-2 Gene Products .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .... 246 STRUCTURAL STUDIES OF THE GENE PRODUCTS FROM THE H-2 MUTANTS . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . ... . . . . . . . . . . .. . . . . . . . . . .. . . .. . . . . 250 The H-2J(b Mutant Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . ... . . . . . . . . . . . . . . . . . . .. . .. .. . . . . . . . .. . . . . . . . . . . . ... . . . 250 Methods for biochemical analysis of the B-2 mutants . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . .. . . . . 251 The bm3 and bmll mutants .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . .. . . . . .. . . . . . . . .. 252 The bm1 and bm2 mutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 256 The bm5. bm6. bm7, bm9. and bm16 mutants 258 The bm4, bm8. and bm10 mutants . . . . .. . . .. . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . .. . . . . . ... . . . 260 Specific conclusions from the studies of the B-2K' mutants . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. .. . . 261 The D-Region Mutants . . . . ... . . . . . . . . . . .. . . . . .. . . . . . . .. . . . . . . . ... . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . ... . . . 263 Other H-2 Mutants . . .. . . . . . . . . . .. . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. .. . . . .. . . . . . . . . .. . . . .. . . ... . . . . . . . . 268 SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . .. . .. . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

Biochemistry of the gene products from murine mhc mutants

Eight newH-2 mutations are reported, five derived fromH-2

 b
 and three fromH-2

 d
 . TheH-2

 b
 
mutants (H-2

 bg
 3,H-2

 bi
 ,H-2

 bj
 ,H-2

 bk
 , andH-2

 bn
 ) were all of the gain+loss type, and all exceptH-2

 bn
 were at the same locus asH-2

 ba
 , associated with theK end. In addition,H-2

bg3 was histocompatible with previously reported mutationsH-2

bg1 andH-2

bg2. The MST for mutant grafts on normal hosts was 2 to 5 weeks. TheH-2

 d
 mutations consisted of two losses (H-2

 db
 ,H-2

 bc
 and one gain + loss (H-2

 dd
 ). They involved at least two, possibly three, loci and have MSTs of less than two weeks. All mutations were recovered in (C57BL/6Kh x BALB/cKh)F1 hybrids, exceptH-2

 db
 , which was isolated on a pure BALB/c background.

Eight new histocompatibility mutations associated with the H-2 complex

The line B6.M505 is congenic with C57BL/6JY and carries a mutant form of theH-2

 b
 haplotype designatedH-2

 bd
 . The mutant site 505 was located by the F1 tests in theK end of theH-2 gene complex. The M505 mice are histoincompatible with the B6.C(Hz1) line (haplotypeH-2

 ba
 ) carrying another mutation in theK end ofH-2

 b
 . Inability of M505 to complement Hz1 in tests with B6 skin grafting is considered as an evidence that the same gene was altered by both mutations. The gained H antigens of two mutants can cross-react in vivo as revealed by accelerated rejection of Hz1 skin grafts by B6 recipients presensitized with M505 spleen cells. The lost antigenic determinants are not identical as shown by accelerated rejection of B6 skin grafts by Hz1 hosts preimmunized with M505 spleen cells. Absorptions of the antiserum ASY-015, (d×a) anti-i, anti-H-2.33 with M505 spleen cells did not clear forH-2

 i
 ,H-2

 b
 andH-2

 ba
 , and absorptions with Hz1 did not clear forH-2

 i
 ,H-2

 b
 , andH-2

 bd
 . These results show that changes of histocompatibility determinants may be accompanied by loss of some haptenic determinants in the Hz1 and M505 mutations.

Study of H-2 mutations in mice. IV. A comparison of the mutants M505 and Hz1 by skin grafting and serological techniques

Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction in the skeletal muscles of dystrophin-deficient mdx mice is accompanied by a reduction in K+ transport and a decrease in its content in the matrix. This is associated with a decrease in the expression of the mitochondrial large-conductance calcium-activated potassium channel (mitoBKCa) in the muscles of mdx mice, which play an important role in cytoprotection. We observed that the BKCa activator NS1619 caused a normalization of mitoBKCa expression and potassium homeostasis in the muscle mitochondria of these animals, which was accompanied by an increase in the calcium retention capacity, mitigation of oxidative stress, and improvement in mitochondrial ultrastructure. This effect of NS1619 contributed to the reduction of degeneration/regeneration cycles and fibrosis in the skeletal muscles of mdx mice as well as a normalization of sarcomere size, but had no effect on the leakage of muscle enzymes and muscle strength loss. In the case of wild-type mice, we noted the negative effect of NS1619 manifested in the inhibition of the functional activity of mitochondria and disruption of their structure, which, however, did not significantly affect the state of the skeletal muscles of the animals. This article discusses the role of mitoBKCa in the development of DMD and the prospects of the approach associated with the correction of its function in treatments of this secondary channelopathy.

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BKCa Activator NS1619 Improves the Structure and Function of Skeletal Muscle Mitochondria in Duchenne Dystrophy

Duchenne muscular dystrophy is caused by the loss of functional dystrophin that secondarily causes systemic metabolic impairment in skeletal muscles and cardiomyocytes. The nutraceutical approach is considered as a possible complementary therapy for this pathology. In this work, we have studied the effect of pyrimidine nucleoside uridine (30 mg/kg/day for 28 days, i.p.), which plays an important role in cellular metabolism, on the development of DMD in the skeletal muscles of dystrophin deficient mdx mice, as well as its effect on the mitochondrial dysfunction that accompanies this pathology. We found that chronic uridine administration reduced fibrosis in the skeletal muscles of mdx mice, but it had no effect on the intensity of degeneration/regeneration cycles and inflammation, pseudohypetrophy, and muscle strength of the animals. Analysis of TEM micrographs showed that uridine also had no effect on the impaired mitochondrial ultrastructure of mdx mouse skeletal muscle. The administration of uridine was found to lead to an increase in the expression of the Drp1 and Parkin genes, which may indicate an increase in the intensity of organelle fission and the normalization of mitophagy. Uridine had little effect on OXPHOS dysfunction in mdx mouse mitochondria, and moreover, it was suppressed in the mitochondria of wild type animals. At the same time, uridine restored the transport of potassium ions and reduced the production of reactive oxygen species; however, this had no effect on the impaired calcium retention capacity of mdx mouse mitochondria. The obtained results demonstrate that the used dose of uridine only partially prevents mitochondrial dysfunction in skeletal muscles during Duchenne dystrophy, though it mitigates the development of destructive processes in skeletal muscles.

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The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy

The present study describes the in vivo effect of triclosan on the frog Xenopus laevis (Daudin, 1802). We have found a dose-dependence of the effect of triclosan on the survival of frogs. At a dose of 2 mg/L, the death of frogs was observed already on the 4th day of the experiment, while at a concentration of 0.5 mg/L, the frogs remained viable for 11 days. Triclosan caused damage to the liver tissue, which was expressed in an increase in the area of hemorrhage and the number of melanomacrophage centers. 0.5 mg/L of this agent did not affect the number of frog red blood cells, but reduced their osmotic resistance. Keeping animals in water containing triclosan (0.5 mg/L for 96 h) led to the suppression of the state 3 respiration rate of frog liver mitochondria. This effect was accompanied by suppression of the combined activity of complexes II and III of the mitochondrial respiratory chain. In parallel with this, we observed a reduction in the Ca2+ retention capacity of frog liver mitochondria, indicating a decrease in the resistance of organelles to mitochondrial permeability transition pore opening. The paper discusses the effects of triclosan on aquatic organisms. 

An in vivo study of the toxic effects of triclosan on Xenopus laevis (Daudin, 1802) frog: Assessment of viability, tissue damage and mitochondrial dysfunction.

A. A. Vedernikov

Papers

Study of H-2 mutations in mice. IV. A comparison of the mutants M505 and Hz1 by skin grafting and serological techniques

BKCa Activator NS1619 Improves the Structure and Function of Skeletal Muscle Mitochondria in Duchenne Dystrophy

The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy

An in vivo study of the toxic effects of triclosan on Xenopus laevis (Daudin, 1802) frog: Assessment of viability, tissue damage and mitochondrial dysfunction.

Unidirectional skin graft incompatibility between theH-2 i5 andH-2 i7 mouse haplotypes