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The Importance of Hl-A Antigens in Ophthalmology
AMERICAN JOURNAL OF OPHTHALMOLOGY FRANK
W.
NEWELL,
Editor-in-Chief
233 East Ontario St., Chicago, Illinois 60611 EDITORIAL BOARD Mathea Allansmith, Boston Douglas R. Anderson, Miami Crowell Beard, San Jose Bernard Becker, St. Louis Frederick C. Blodi. Iowa City Benjamin F. Boyd, Panama Charles J. Campbell, New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Sir Stewart Duke-Elder, London J. Terry Ernest, Chicago
DuPont Guerry III, Richmond Paul Henkind, Bronx Michael J. Hogan, San Francisco Robert W. Hollenhorst, Rochester Herbert E. Kaufman, Gainesville Arthur H. Keeney, Louisville Bertha A. Klien, Tucson Carl Kupfer, Bethesda James E. Lebensohn, Chicago Irving H. Leopold, Irvine A. Edward Maumenee, Baltimore
Edward W. D. Norton, Miami Arnall Patz, Baltimore Steven M. Podos, New York Albert M. Potts, Louisville Algernon B. Reese, New York Robert D. Reinecke, Albany Marvin L. Sears, Neiv Haven David Shoch, Chicago Bruce E. Spivey, San Francisco Bradley R. Straatsma.Loj Angeles Gunter K. von Noorden, Houston
Published monthly by the Ophthalmic Publishing Company 233 East Ontario St., Chicago, Illinois 60611 Directors:
A. EDWARD MAUMENEE. President; MICHAEL J. HOGAN, Vice-President; FRANK W. NEWELL,
Secretary and Treasurer; Edward W. D. NORTON, DAVID SHOCH, BRADLEY R. STRAATSMA
T H E IMPORTANCE O F HL-A ANTIGENS IN OPHTHALMOLOGY Evidence linking histocompatibility ( H L A) antigens with various disease entities is being published with increasing frequency.1"5 An individual inherits maternal and paternal genes that determine the histocompatibility complex. This complex consists of serologically and lymphocyte defined (SD and LD) antigens that are cell membrane determinants controlled by genes on chromosomes near the I r genes regulating the immune response.M•6•7 The membrane determinants exist on every nucleated cell, although they may not be equally abundant on all cells. Human leukocyte antigens (HL-A) gave the first SD series its name when the genetic locus was termed LA (locus A ) . Locus FOUR controls the second SD series of antigens and both series consist of many alleles. In addition to the strong LA and FOUR SD antigens, an individual's phenotype comprises a strong LD, as well as weaker SD and LD antigens (Figure). Histocompatibility typing became more
important as renal transplantation increased in frequency.8 The antigens are under con stant study and form the subject of yearly workshops where newly discovered SD and LD antigens are discussed, compared, and given official names. Corneal grafts have not stimulated undue immunologic problems. The success of the corneal graft appears to de pend on factors other than histocompatibility antigens such as the surgeon's operative skill plus the use of immunosuppressive therapy (usually systemic or topical corticosteroids, or both).9-10 Vascularization and inflammation of the cornea bring leukocytes to the area. The "privilege of the cornea" may reflect the lack of encounter of the patient's lymphocytes with corneal proteins. They appear to become sensitized on exposure to cornea in the af ferent arc of the immune response. Per sistence or recurrence of corneal vasculariza tion will bring antibody, antibody bearing, and lymphokine secreting lymphocytes to the cornea (the efferent arc of the immune re sponse). At that time, anticorneal antibody,
774
VOL. 80, NO. 4
775
EDITORIAL
which can diffuse into the cornea from im munity, may be important in the pathophysiology of chronic keratitis. 10-14 Similarly, vascularization may cause the histocompatibility antigens to become of greater impor tance in graft survival or rejection.11 In histocompatibility testing an individual's cells, usually peripheral lymphocytes, are tested with standardized antisera against t' » known SD allotypes of the LA and F O U l i series.1 Mixed lymphocyte cultures are per formed by incubating an individual's lympho cytes with prepared stimulator cells to detect the LD antigens. The test can be inhibited by serum containing antibodies to SD loci although the cells remain viable. Mixed lymphocyte cultures can be linked to a host cell-donor relationship in which only cell con tact reveals the membrane determinant. The brief description of the tests permits under
standing of why an individual who has re cently been transfused may have foreign cells in his circulation with SD and LD antigens, which will stimulate antibody secretion and cellular immunity. HL-A antigens are not as strong antigenically as the A-B-0 red blood cell anti gens and rarely lead to anaphylactic reactions. Maternal sensitization to fetal antigens (pa ternally derived) provides many of the antisera used to test for SD antigens. Whether maternal antibodies to paternal fetal antigens affect the fetus is a matter of debate, par ticularly regarding infants with immuno deficiency disease.15 The HL-A antigen is composed of two polypeptide chains. One chain has a molecu lar weight of 34,000, the other of 12,000. The latter is identical to (3-2 microglobulin, which has an amino acid sequence resembling a
CHROMOSOMES PATERNAL MATERNAL ALLELES First series 1,2,3,9 (W23.W24), 10 (W25.W2*), 11, W28,W29,W30,W3I,W32,W 9.6 etc.
LOCUS:' LA Figure (Henley and Leopold). Segment of chromosomes to indi cate close relationship of histo compatibility genes and Ir gene. The exact location of Ir genes with respect to histocompatibility genes is not known. Nomenclature for the SD antigens controlled by the LA and FOUR loci was determined by the World Health Organization. HL-A initials are not indicated, only numbers are shown for es tablished specificities. "W" designa tion is for new specificities, which originate in the yearly workshops and will be given an HL-A designa tion when thoroughly defined.
Weak MLC
} Number unknown
} >5
AJ
ym I Four H \ ^ J Strong MLC
J ?lr
Second series series Second 5,7,8,I2,I3,W5,WI0,WI4,WI3, WI6,WI7,WI8,W2l,W22,W27,etc.
} Number unknown I
! I « Serologically defined determinants • Lymphocyte defined determinants
776
AMERICAN JOURNAL OF OPHTHALMOLOGY
constant domain of the y heavy chain of immunoglobulins.16'17 The structure of the antigen recalls that of the immunoglobulin molecule and the close chromosomal relation ship of the genetic loci for histocompatibility and the Ir gene.1'4'6-7 The Ir gene does not control immunoglobulin structure but the type of immune response, that is, the class of antibody or the types of lymphokine se creted. The association of some HL-A antigens with disorders attributed to aberrations of the immune response has led to worldwide research. Different population groups bear different HL-A antigens and it becomes criti cal to correlate not only the prevalence of certain HL-A antigens with disease states but also with their incidence in a similar population group.18"20 Refined statistical analytic methods have been outlined which take into consideration (1) the allotype's incidence in a strictly con trolled normal population, (2) the associa tion of SD allotypes controlled by the two stronger histocompatibility loci with each other, and (3) the mathematical correction for the number of allotypes tested.1*3'5'21'22 An unpublished report by Aviner, Henley, Fotino, and Leopold outlines the meticulous statistical study which must be performed. A group of disorders considered to be due to or associated with immunologic aberra tions, as well as a variety of tumors, in par ticular lymphomas, have been studied criti cally.1"5-23 The arthritides—ankylosing spondylitis, rheumatoid arthritis—are among the first group of diseases mentioned and are as sociated with HL-A 27.7 This antigen may be of etiologic significance or it may permit an immune response leading to injury of these tissues and it may also be of impor tance in acute anterior uveitis.24 Hereditary disorders, such as diabetes mellitus, have been carefully investigated and a strong as sociation of HL-A8 or W15, or both, with juvenile insulin-dependent diabetes now seems to be established.25"27 Whether the HL-A antigen renders this population more
OCTOBER, 1975
prone to (virus) infections that injure the islets of Langerhans, or whether the immune response in these patients makes them more susceptible to infectious damage of this tis sue or whether the immune response itself is the cause of the injury is not known.28 A few patients and controls can demon strate the reality of the association between disease and the HL-A serotype when it is strong, as is the case in ankylosing spondylitis and HL-A 27. 7 Problems of sampling are less important than in instances where the association is not so strong, as in a multifactorial hereditary disorder, such as openangle glaucoma.29"32 The same mechanisms listed for diabetes may be responsible. An increased incidence of some HL-A antigens compared to the normal population is in adequate to associate them with open-angle glaucomas.33'34 One statistical analysis sug gests an association of W5 with open-angle glaucoma (Aviner, Henley, Fotino, and Leopold, unpublished data). The diagnosis of open-angle glaucoma is not always established in the same manner by different ophthalmologists. The findings pre sented in preliminary reports are not in agree ment.33-34 An intensive collaborative effort to link HL-A antigens with the presence of open-angle glaucoma appears justified. It should include susceptibility to the disorder, as detected by in vivo water provocation and steroid tests and other in vitro tests35 (Aviner, Leopold, Okas, and Henley, unpublished data). In order to establish a large, hetero geneous patient population, cooperative stud ies among several university centers should evaluate not only the patient with open-angle glaucoma and the susceptible patient, but also his relatives in thorough family studies which will determine whether genes play a role in open-angle glaucoma. Similarly, a cooperative study may discern HL-A allotypes which may render patients more susceptible to the de velopment of secondary intraocular -hyper tension. WALTER L. HENLEY IRVING H. LEOPOLD
EDITORIAL
VOL. 80, NO. 4 REFERENCES
1. van Rood, J. J., van Hooff, J. P., and Keuning, J. J.: Disease predisposition, immune responsiveness and the fine structure of the HL-A supergene. Transplant. Rev. 22:75, 1975. 2. Dausset, J., Degos, L., and Hors, J.: The association of the HL-A antigens and diseases. Clin. Immunol. Immunopathol. 3:127, 1974. 3. Svejgaard, A., Plate, P., Ryder, L. P., Niel sen, L. S., and Thomsen, M.: HL-A and disease associations—a survey. Transplant. Rev. 22:3, 1975. 4. McDevitt, H. O., and Bodner, W. F.: HL-A, immune response genes, and disease. Lancet 1:1269, 1974. 5. Dausset, J,, and Hors, J.: Some contributions of the HL-A complex to the genetics of human diseases. Transplant. Rev. 22:44, 1975. 6. Buckley, C. E., Ill, Dorsey, F. C, Corley, R. B., Ralph, W. B., Woodbury, M. A., and Amos, D. B.: HL-A linked human immune-re sponse genes. Proc. Natl. Acad. Sci. U.S.A. 70: 2157, 1973. 7. Lockshin, M. D., Fotino, M., Gough, W. W., and Litwin, S. D.: Ankylosing spondylitis and HL-A. A genetic disease plus ? Am. J. Med. 58:695, 1975. 8. Scandia Transplant Report: HL-A matching and kidney-graft survival. Lancet 2:240, 1975. 9. Allansmith, M. R., Fine, M., and Payne, R.: Histocompatibility typing and corneal transplanta tion. Trans. Am. Acad. Ophthalmol. Otolaryngol. 78:445, 1974. 10. Gibbs, D. C, Batchelor, J. R., and Casey, T. A.; The influence of HL-A compatibility on the fate of corneal grafts. In Ciba Foundation Symposium on Corneal Graft Failure. London, Associated Scientific Publishers, 1973, vol. 15, pp. 293-304. 11. Ehlers, N., and Ahrons, S.: Corneal trans plantation and histocompatibility. Acta Ophthalmol. 49:513, 1971. 12. Elliot, J. H.: Immune factors in corneal graft rejection. Invest. Ophthalmol. 10:216, 1971. 13. Henley, W. L., Shore, B., and Leopold, I. H.: Inhibition of leucocyte migration by corneal antigen in chronic viral keratitis. Nature New Biol. 233:38, 1971. 14. Maumenee, A. E.: The influence of donorrecipient sensitization on corneal grafts. Am. J. Ophthalmol. 34:142, 1951. 15. Terasaki, P. I., Miyajima, T., Sengar, D. P. S., and Stiehm, E. R.: Extraneous lymphocytic HL-A antigens in severe combined immuno deficiency disease. Transplantation 13:250, 1972. 16. Poulik, M. D., Ferrone, S., Pellegrino, M. A., Sevier, D. E., Oh, S. K., and Reisfeld, R. A.: Association of HL-A antigens and Bj-microglobulin. Concepts and questions. Transplant. Rev. 21:106, 1974. 17. Strominger, J. L., Cresswell, P., Grey, H., Humphreys, R. E.: The immunoglobulin-like struc ture of human histocompatibility antigens. Trans plant. Rev. 21:126, 1974.
777
18. Bodmer, W. F.: Population genetics of the HL-A system: Retrospect and prospect. Histo compatibility testing. Report of International Work shop and Conference. Copenhagen, Munksgaard, 1972, p. 612. 19. Albert, E. D., Mickey, M. R., and Terasaki, P. I.: Genetics of the HL-A Americans, American Negroes, and Mexican Americans. Histocompati bility testing. Report of International Workshop and Conference. Copenhagen, Munksgaard, 1972, p. 233. 20. Degos, L., and Dausset, J.: Human migra tions and linkage disequilibrium of HL-A system. Immunogenetics 3:195, 1974. 21. Svejgaard, A., Jersild, C, Staub-Nielsen, L., and Bodmer, W. F.: HL-A antigens. Tissue anti gens 4:95, 1974. 22. Belvedere, M. C, Curtoni, E. S., Dausset, J.: On the heterogeneity of linkage estimations between LA and FOUR loci of the HL-A system. Tissue Antigens 5:99,1975. 23. Terasaki, P. I., and Mickey, M. R.: HL-A halotypes of 32 diseases. Transplant. Rev. 22:105, 1975. 24. Brewerton, D. A., Caffrey, M., Nicholls, A., Walters, D., and James, D. C. O.: Acute anterior uveitis and HL-A 27. Lancet 2:994, 1973. 25. Singal, D. P., and Blajchman, M. A.: Histo compatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22:429, 1973. 26. Nerup, J., Platz, P., Andersen, O. R., Christy, M., Lynges, O. E., Paulson, J. E., Thomsen, M., Neilson, L. S., Svejgaard, A., and Ryder, L. P.: HL-A antigens and diabetes mellitus. Lancet 2:864, 1974. 27. Thomsen, M., Platz, P., Andersen, O. R., Christy, M., Lynges, O. E., Nerup, J. Rasmussen, K., Ryder, L. P., Neilson, L. S., and Svejgaard, A.: MLC typing in juvenile diabetes mellitus and idiopathic Addison's disease. Transplant. Rev. 22:29, 1975. 28. Kaufman, H. E.: Genetic inflammatory dis ease. Invest. Ophthalmol. 13:555, 1974. 29. Francois, J. F.: Genetics and primary openangle glaucoma. Am. J. Ophthalmol. 61:622, 1966. 30. Becker, B.: The genetic problem of chronic simple glaucoma. In Salanes, M. I. (ed.) : XXI Concilium Ophthalmologicum (Mexico, 1970). Am sterdam, Excerpta Medica, 1971, p. 278. 31. Armaly, M. F.: The genetic problem of chronic simple glaucoma. In Salones, M. I. (ed.): XXI Concilium Ophthalmologicum (Mexico, 1970). Amsterdam, Excerpta Medica, 1971, p. 278. 32. Tomlinson, A., and Leighton, D. A.: Ocular dimensions and the heredity of open-angle glau coma. Br. J. Ophthalmol. 58:68, 1974. 33. Henley, W. L., Leopold, I. H., and Aviner, Z.: Glaucoma and HL-A antigens. Lancet 2:1273, 1974. 34. Waltman, S. R., Palmberg, P., Newton, W., and Becker, B.: Glaucoma and HL-A antigens. Lancet 1:927, 1975. 35. Bigger, J. F., Palmberg, P. F., and Zink,
AMERICAN JOURNAL OF OPHTHALMOLOGY
778
H. A.: In vitro corticosteroids. Correlation re sponse with primary open-angle glaucoma and ocu lar corticosteroid sensitivity. Am. J. Ophthalmol. 79:92, 1975.
CORRESPONDENCE Letters to the Editor must be typed double-spaced on 8V& X 11-inch bond paper; with IVi-inch margins on all four sides, and limited in length to two manuscript pages.
OCTOBER, 1975
vation of the eyelid may be seen after 24 hours, depending on the extent of the tar sal resection, the severity of the blepharopto sis, and the amount of levator function. The elimination of the suture prevents the only serious complication of the FasanellaServat procedure and further simplifies an already "simplified operation." 1 LEWIS LAURING,
M.D.
San Francisco, California REFERENCES
SUTURELESS FASANELLA-SERVAT BLEPHAROPTOSIS CORRECTION
Editor: The Fasanella-Servat procedure1 intro duced in 1961 is widely accepted for cases of minimal blepharoptosis if the levator func tion is good. Many modifications2-6 in the original suturing technique have been offered to avoid the sometimes severe postoperative keratitis resulting from suture material abrading the cornea. I recently discovered that the FasanellaServat operation can be performed without the use of any sutures and yet the good re sults obtained with this procedure have not been compromised. The essentials of my tech nique are as follows: After everting the upper eyelid, approxi mately 0.5 ml of 2% lidocaine with epinephrine is injected subconjunctivally along the superior tarsal border. Two curved hemostats are placed in the standard manner1'3"4 and allowed to remain tightly clamped for one minute. Straight, sharply pointed scissors is used to excise the tarsus by cutting in the center of the broad groove remaining in the tarsus after the removal of the hemostats. Bleeding, if any, is minimal and the cut ends of the tarsus and conjunctiva-Muller's mus cle remain adherent. An antibiotic ointment is instilled and the eyelid is returned to its normal position. The eye is patched for 24 hours; a Frost suture is optional. The maximal effect of this operation is apparent in three weeks although some ele-
1. Fasanella, R. M., and Servat, J.: Levator resection for minimal ptosis. Another simplified op eration. Arch. Ophthalmol. 65:493, 1961. 2. Callahan, A.: Reconstructive Surgery of the Eyelids and Ocular Adnexa. Birmingham, Aescu lapius, 1966, p. 86. 3. Beard, C.: Ptosis. St. Louis, C. V. Mosby, 1969, pp. 136-138. 4. : Blepharoptosis repair by modified Fasanella-Servat operation. Am. J. Ophthalmol. 69:850, 1970. 5. Fasanella, R. M.: Surgery for minimal ptosis. The Fasanella-Servat operation, 1973. Trans. Oph thalmol. Soc. U.K. 93:425, 1973. 6. Crawford, J. S.: Repair of blepharoptosis with a modification of the Fasanella-Servat operation. Can. J. Ophthalmol. 8:19, 1973. NITROUS OXIDE ANESTHESIA W I T H G A S IN THE VITREOUS CAVITY*
Editor: We wish to emphasize the danger of using nitrous oxide anesthesia when gas is present in the vitreous cavity. Since nitrous oxide is extremely soluble, it will diffuse rapidly into a body space containing a less soluble gas, thus causing rapid expansion of the gas pocket. Smith, Carl, Linn, and Nemoto in their article, "Effect of Nitrous Oxide on Air in Vitreous" (Am. J. Ophthalmol. 78: 314, 1974), reported a significant rise in intraocular pressure during nitrous oxide anesthesia in rhesus monkey eyes containing intravitreal air. The authors speculated that the increase in intraocular pressure if SF 6 were present in the vitreous cavity would be at least as great as that with intravitreal air. We have inadvertently documented this po tential surgical hazard with intraocular SF 6 . A patient had a vitrectomy for a nonclear-
W.
NEWELL,
Editor-in-Chief
233 East Ontario St., Chicago, Illinois 60611 EDITORIAL BOARD Mathea Allansmith, Boston Douglas R. Anderson, Miami Crowell Beard, San Jose Bernard Becker, St. Louis Frederick C. Blodi. Iowa City Benjamin F. Boyd, Panama Charles J. Campbell, New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Sir Stewart Duke-Elder, London J. Terry Ernest, Chicago
DuPont Guerry III, Richmond Paul Henkind, Bronx Michael J. Hogan, San Francisco Robert W. Hollenhorst, Rochester Herbert E. Kaufman, Gainesville Arthur H. Keeney, Louisville Bertha A. Klien, Tucson Carl Kupfer, Bethesda James E. Lebensohn, Chicago Irving H. Leopold, Irvine A. Edward Maumenee, Baltimore
Edward W. D. Norton, Miami Arnall Patz, Baltimore Steven M. Podos, New York Albert M. Potts, Louisville Algernon B. Reese, New York Robert D. Reinecke, Albany Marvin L. Sears, Neiv Haven David Shoch, Chicago Bruce E. Spivey, San Francisco Bradley R. Straatsma.Loj Angeles Gunter K. von Noorden, Houston
Published monthly by the Ophthalmic Publishing Company 233 East Ontario St., Chicago, Illinois 60611 Directors:
A. EDWARD MAUMENEE. President; MICHAEL J. HOGAN, Vice-President; FRANK W. NEWELL,
Secretary and Treasurer; Edward W. D. NORTON, DAVID SHOCH, BRADLEY R. STRAATSMA
T H E IMPORTANCE O F HL-A ANTIGENS IN OPHTHALMOLOGY Evidence linking histocompatibility ( H L A) antigens with various disease entities is being published with increasing frequency.1"5 An individual inherits maternal and paternal genes that determine the histocompatibility complex. This complex consists of serologically and lymphocyte defined (SD and LD) antigens that are cell membrane determinants controlled by genes on chromosomes near the I r genes regulating the immune response.M•6•7 The membrane determinants exist on every nucleated cell, although they may not be equally abundant on all cells. Human leukocyte antigens (HL-A) gave the first SD series its name when the genetic locus was termed LA (locus A ) . Locus FOUR controls the second SD series of antigens and both series consist of many alleles. In addition to the strong LA and FOUR SD antigens, an individual's phenotype comprises a strong LD, as well as weaker SD and LD antigens (Figure). Histocompatibility typing became more
important as renal transplantation increased in frequency.8 The antigens are under con stant study and form the subject of yearly workshops where newly discovered SD and LD antigens are discussed, compared, and given official names. Corneal grafts have not stimulated undue immunologic problems. The success of the corneal graft appears to de pend on factors other than histocompatibility antigens such as the surgeon's operative skill plus the use of immunosuppressive therapy (usually systemic or topical corticosteroids, or both).9-10 Vascularization and inflammation of the cornea bring leukocytes to the area. The "privilege of the cornea" may reflect the lack of encounter of the patient's lymphocytes with corneal proteins. They appear to become sensitized on exposure to cornea in the af ferent arc of the immune response. Per sistence or recurrence of corneal vasculariza tion will bring antibody, antibody bearing, and lymphokine secreting lymphocytes to the cornea (the efferent arc of the immune re sponse). At that time, anticorneal antibody,
774
VOL. 80, NO. 4
775
EDITORIAL
which can diffuse into the cornea from im munity, may be important in the pathophysiology of chronic keratitis. 10-14 Similarly, vascularization may cause the histocompatibility antigens to become of greater impor tance in graft survival or rejection.11 In histocompatibility testing an individual's cells, usually peripheral lymphocytes, are tested with standardized antisera against t' » known SD allotypes of the LA and F O U l i series.1 Mixed lymphocyte cultures are per formed by incubating an individual's lympho cytes with prepared stimulator cells to detect the LD antigens. The test can be inhibited by serum containing antibodies to SD loci although the cells remain viable. Mixed lymphocyte cultures can be linked to a host cell-donor relationship in which only cell con tact reveals the membrane determinant. The brief description of the tests permits under
standing of why an individual who has re cently been transfused may have foreign cells in his circulation with SD and LD antigens, which will stimulate antibody secretion and cellular immunity. HL-A antigens are not as strong antigenically as the A-B-0 red blood cell anti gens and rarely lead to anaphylactic reactions. Maternal sensitization to fetal antigens (pa ternally derived) provides many of the antisera used to test for SD antigens. Whether maternal antibodies to paternal fetal antigens affect the fetus is a matter of debate, par ticularly regarding infants with immuno deficiency disease.15 The HL-A antigen is composed of two polypeptide chains. One chain has a molecu lar weight of 34,000, the other of 12,000. The latter is identical to (3-2 microglobulin, which has an amino acid sequence resembling a
CHROMOSOMES PATERNAL MATERNAL ALLELES First series 1,2,3,9 (W23.W24), 10 (W25.W2*), 11, W28,W29,W30,W3I,W32,W 9.6 etc.
LOCUS:' LA Figure (Henley and Leopold). Segment of chromosomes to indi cate close relationship of histo compatibility genes and Ir gene. The exact location of Ir genes with respect to histocompatibility genes is not known. Nomenclature for the SD antigens controlled by the LA and FOUR loci was determined by the World Health Organization. HL-A initials are not indicated, only numbers are shown for es tablished specificities. "W" designa tion is for new specificities, which originate in the yearly workshops and will be given an HL-A designa tion when thoroughly defined.
Weak MLC
} Number unknown
} >5
AJ
ym I Four H \ ^ J Strong MLC
J ?lr
Second series series Second 5,7,8,I2,I3,W5,WI0,WI4,WI3, WI6,WI7,WI8,W2l,W22,W27,etc.
} Number unknown I
! I « Serologically defined determinants • Lymphocyte defined determinants
776
AMERICAN JOURNAL OF OPHTHALMOLOGY
constant domain of the y heavy chain of immunoglobulins.16'17 The structure of the antigen recalls that of the immunoglobulin molecule and the close chromosomal relation ship of the genetic loci for histocompatibility and the Ir gene.1'4'6-7 The Ir gene does not control immunoglobulin structure but the type of immune response, that is, the class of antibody or the types of lymphokine se creted. The association of some HL-A antigens with disorders attributed to aberrations of the immune response has led to worldwide research. Different population groups bear different HL-A antigens and it becomes criti cal to correlate not only the prevalence of certain HL-A antigens with disease states but also with their incidence in a similar population group.18"20 Refined statistical analytic methods have been outlined which take into consideration (1) the allotype's incidence in a strictly con trolled normal population, (2) the associa tion of SD allotypes controlled by the two stronger histocompatibility loci with each other, and (3) the mathematical correction for the number of allotypes tested.1*3'5'21'22 An unpublished report by Aviner, Henley, Fotino, and Leopold outlines the meticulous statistical study which must be performed. A group of disorders considered to be due to or associated with immunologic aberra tions, as well as a variety of tumors, in par ticular lymphomas, have been studied criti cally.1"5-23 The arthritides—ankylosing spondylitis, rheumatoid arthritis—are among the first group of diseases mentioned and are as sociated with HL-A 27.7 This antigen may be of etiologic significance or it may permit an immune response leading to injury of these tissues and it may also be of impor tance in acute anterior uveitis.24 Hereditary disorders, such as diabetes mellitus, have been carefully investigated and a strong as sociation of HL-A8 or W15, or both, with juvenile insulin-dependent diabetes now seems to be established.25"27 Whether the HL-A antigen renders this population more
OCTOBER, 1975
prone to (virus) infections that injure the islets of Langerhans, or whether the immune response in these patients makes them more susceptible to infectious damage of this tis sue or whether the immune response itself is the cause of the injury is not known.28 A few patients and controls can demon strate the reality of the association between disease and the HL-A serotype when it is strong, as is the case in ankylosing spondylitis and HL-A 27. 7 Problems of sampling are less important than in instances where the association is not so strong, as in a multifactorial hereditary disorder, such as openangle glaucoma.29"32 The same mechanisms listed for diabetes may be responsible. An increased incidence of some HL-A antigens compared to the normal population is in adequate to associate them with open-angle glaucomas.33'34 One statistical analysis sug gests an association of W5 with open-angle glaucoma (Aviner, Henley, Fotino, and Leopold, unpublished data). The diagnosis of open-angle glaucoma is not always established in the same manner by different ophthalmologists. The findings pre sented in preliminary reports are not in agree ment.33-34 An intensive collaborative effort to link HL-A antigens with the presence of open-angle glaucoma appears justified. It should include susceptibility to the disorder, as detected by in vivo water provocation and steroid tests and other in vitro tests35 (Aviner, Leopold, Okas, and Henley, unpublished data). In order to establish a large, hetero geneous patient population, cooperative stud ies among several university centers should evaluate not only the patient with open-angle glaucoma and the susceptible patient, but also his relatives in thorough family studies which will determine whether genes play a role in open-angle glaucoma. Similarly, a cooperative study may discern HL-A allotypes which may render patients more susceptible to the de velopment of secondary intraocular -hyper tension. WALTER L. HENLEY IRVING H. LEOPOLD
EDITORIAL
VOL. 80, NO. 4 REFERENCES
1. van Rood, J. J., van Hooff, J. P., and Keuning, J. J.: Disease predisposition, immune responsiveness and the fine structure of the HL-A supergene. Transplant. Rev. 22:75, 1975. 2. Dausset, J., Degos, L., and Hors, J.: The association of the HL-A antigens and diseases. Clin. Immunol. Immunopathol. 3:127, 1974. 3. Svejgaard, A., Plate, P., Ryder, L. P., Niel sen, L. S., and Thomsen, M.: HL-A and disease associations—a survey. Transplant. Rev. 22:3, 1975. 4. McDevitt, H. O., and Bodner, W. F.: HL-A, immune response genes, and disease. Lancet 1:1269, 1974. 5. Dausset, J,, and Hors, J.: Some contributions of the HL-A complex to the genetics of human diseases. Transplant. Rev. 22:44, 1975. 6. Buckley, C. E., Ill, Dorsey, F. C, Corley, R. B., Ralph, W. B., Woodbury, M. A., and Amos, D. B.: HL-A linked human immune-re sponse genes. Proc. Natl. Acad. Sci. U.S.A. 70: 2157, 1973. 7. Lockshin, M. D., Fotino, M., Gough, W. W., and Litwin, S. D.: Ankylosing spondylitis and HL-A. A genetic disease plus ? Am. J. Med. 58:695, 1975. 8. Scandia Transplant Report: HL-A matching and kidney-graft survival. Lancet 2:240, 1975. 9. Allansmith, M. R., Fine, M., and Payne, R.: Histocompatibility typing and corneal transplanta tion. Trans. Am. Acad. Ophthalmol. Otolaryngol. 78:445, 1974. 10. Gibbs, D. C, Batchelor, J. R., and Casey, T. A.; The influence of HL-A compatibility on the fate of corneal grafts. In Ciba Foundation Symposium on Corneal Graft Failure. London, Associated Scientific Publishers, 1973, vol. 15, pp. 293-304. 11. Ehlers, N., and Ahrons, S.: Corneal trans plantation and histocompatibility. Acta Ophthalmol. 49:513, 1971. 12. Elliot, J. H.: Immune factors in corneal graft rejection. Invest. Ophthalmol. 10:216, 1971. 13. Henley, W. L., Shore, B., and Leopold, I. H.: Inhibition of leucocyte migration by corneal antigen in chronic viral keratitis. Nature New Biol. 233:38, 1971. 14. Maumenee, A. E.: The influence of donorrecipient sensitization on corneal grafts. Am. J. Ophthalmol. 34:142, 1951. 15. Terasaki, P. I., Miyajima, T., Sengar, D. P. S., and Stiehm, E. R.: Extraneous lymphocytic HL-A antigens in severe combined immuno deficiency disease. Transplantation 13:250, 1972. 16. Poulik, M. D., Ferrone, S., Pellegrino, M. A., Sevier, D. E., Oh, S. K., and Reisfeld, R. A.: Association of HL-A antigens and Bj-microglobulin. Concepts and questions. Transplant. Rev. 21:106, 1974. 17. Strominger, J. L., Cresswell, P., Grey, H., Humphreys, R. E.: The immunoglobulin-like struc ture of human histocompatibility antigens. Trans plant. Rev. 21:126, 1974.
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18. Bodmer, W. F.: Population genetics of the HL-A system: Retrospect and prospect. Histo compatibility testing. Report of International Work shop and Conference. Copenhagen, Munksgaard, 1972, p. 612. 19. Albert, E. D., Mickey, M. R., and Terasaki, P. I.: Genetics of the HL-A Americans, American Negroes, and Mexican Americans. Histocompati bility testing. Report of International Workshop and Conference. Copenhagen, Munksgaard, 1972, p. 233. 20. Degos, L., and Dausset, J.: Human migra tions and linkage disequilibrium of HL-A system. Immunogenetics 3:195, 1974. 21. Svejgaard, A., Jersild, C, Staub-Nielsen, L., and Bodmer, W. F.: HL-A antigens. Tissue anti gens 4:95, 1974. 22. Belvedere, M. C, Curtoni, E. S., Dausset, J.: On the heterogeneity of linkage estimations between LA and FOUR loci of the HL-A system. Tissue Antigens 5:99,1975. 23. Terasaki, P. I., and Mickey, M. R.: HL-A halotypes of 32 diseases. Transplant. Rev. 22:105, 1975. 24. Brewerton, D. A., Caffrey, M., Nicholls, A., Walters, D., and James, D. C. O.: Acute anterior uveitis and HL-A 27. Lancet 2:994, 1973. 25. Singal, D. P., and Blajchman, M. A.: Histo compatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22:429, 1973. 26. Nerup, J., Platz, P., Andersen, O. R., Christy, M., Lynges, O. E., Paulson, J. E., Thomsen, M., Neilson, L. S., Svejgaard, A., and Ryder, L. P.: HL-A antigens and diabetes mellitus. Lancet 2:864, 1974. 27. Thomsen, M., Platz, P., Andersen, O. R., Christy, M., Lynges, O. E., Nerup, J. Rasmussen, K., Ryder, L. P., Neilson, L. S., and Svejgaard, A.: MLC typing in juvenile diabetes mellitus and idiopathic Addison's disease. Transplant. Rev. 22:29, 1975. 28. Kaufman, H. E.: Genetic inflammatory dis ease. Invest. Ophthalmol. 13:555, 1974. 29. Francois, J. F.: Genetics and primary openangle glaucoma. Am. J. Ophthalmol. 61:622, 1966. 30. Becker, B.: The genetic problem of chronic simple glaucoma. In Salanes, M. I. (ed.) : XXI Concilium Ophthalmologicum (Mexico, 1970). Am sterdam, Excerpta Medica, 1971, p. 278. 31. Armaly, M. F.: The genetic problem of chronic simple glaucoma. In Salones, M. I. (ed.): XXI Concilium Ophthalmologicum (Mexico, 1970). Amsterdam, Excerpta Medica, 1971, p. 278. 32. Tomlinson, A., and Leighton, D. A.: Ocular dimensions and the heredity of open-angle glau coma. Br. J. Ophthalmol. 58:68, 1974. 33. Henley, W. L., Leopold, I. H., and Aviner, Z.: Glaucoma and HL-A antigens. Lancet 2:1273, 1974. 34. Waltman, S. R., Palmberg, P., Newton, W., and Becker, B.: Glaucoma and HL-A antigens. Lancet 1:927, 1975. 35. Bigger, J. F., Palmberg, P. F., and Zink,
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H. A.: In vitro corticosteroids. Correlation re sponse with primary open-angle glaucoma and ocu lar corticosteroid sensitivity. Am. J. Ophthalmol. 79:92, 1975.
CORRESPONDENCE Letters to the Editor must be typed double-spaced on 8V& X 11-inch bond paper; with IVi-inch margins on all four sides, and limited in length to two manuscript pages.
OCTOBER, 1975
vation of the eyelid may be seen after 24 hours, depending on the extent of the tar sal resection, the severity of the blepharopto sis, and the amount of levator function. The elimination of the suture prevents the only serious complication of the FasanellaServat procedure and further simplifies an already "simplified operation." 1 LEWIS LAURING,
M.D.
San Francisco, California REFERENCES
SUTURELESS FASANELLA-SERVAT BLEPHAROPTOSIS CORRECTION
Editor: The Fasanella-Servat procedure1 intro duced in 1961 is widely accepted for cases of minimal blepharoptosis if the levator func tion is good. Many modifications2-6 in the original suturing technique have been offered to avoid the sometimes severe postoperative keratitis resulting from suture material abrading the cornea. I recently discovered that the FasanellaServat operation can be performed without the use of any sutures and yet the good re sults obtained with this procedure have not been compromised. The essentials of my tech nique are as follows: After everting the upper eyelid, approxi mately 0.5 ml of 2% lidocaine with epinephrine is injected subconjunctivally along the superior tarsal border. Two curved hemostats are placed in the standard manner1'3"4 and allowed to remain tightly clamped for one minute. Straight, sharply pointed scissors is used to excise the tarsus by cutting in the center of the broad groove remaining in the tarsus after the removal of the hemostats. Bleeding, if any, is minimal and the cut ends of the tarsus and conjunctiva-Muller's mus cle remain adherent. An antibiotic ointment is instilled and the eyelid is returned to its normal position. The eye is patched for 24 hours; a Frost suture is optional. The maximal effect of this operation is apparent in three weeks although some ele-
1. Fasanella, R. M., and Servat, J.: Levator resection for minimal ptosis. Another simplified op eration. Arch. Ophthalmol. 65:493, 1961. 2. Callahan, A.: Reconstructive Surgery of the Eyelids and Ocular Adnexa. Birmingham, Aescu lapius, 1966, p. 86. 3. Beard, C.: Ptosis. St. Louis, C. V. Mosby, 1969, pp. 136-138. 4. : Blepharoptosis repair by modified Fasanella-Servat operation. Am. J. Ophthalmol. 69:850, 1970. 5. Fasanella, R. M.: Surgery for minimal ptosis. The Fasanella-Servat operation, 1973. Trans. Oph thalmol. Soc. U.K. 93:425, 1973. 6. Crawford, J. S.: Repair of blepharoptosis with a modification of the Fasanella-Servat operation. Can. J. Ophthalmol. 8:19, 1973. NITROUS OXIDE ANESTHESIA W I T H G A S IN THE VITREOUS CAVITY*
Editor: We wish to emphasize the danger of using nitrous oxide anesthesia when gas is present in the vitreous cavity. Since nitrous oxide is extremely soluble, it will diffuse rapidly into a body space containing a less soluble gas, thus causing rapid expansion of the gas pocket. Smith, Carl, Linn, and Nemoto in their article, "Effect of Nitrous Oxide on Air in Vitreous" (Am. J. Ophthalmol. 78: 314, 1974), reported a significant rise in intraocular pressure during nitrous oxide anesthesia in rhesus monkey eyes containing intravitreal air. The authors speculated that the increase in intraocular pressure if SF 6 were present in the vitreous cavity would be at least as great as that with intravitreal air. We have inadvertently documented this po tential surgical hazard with intraocular SF 6 . A patient had a vitrectomy for a nonclear-