0022-202X/85/ 8404 -0237$02.00/ 0 THE JO URNAL OF I NVESTIGATIVE DEI!MATOLO GY, 84:237- 238, 1985 Copy right © 1985 by The Williams & Wilkins Co.

Vol. 84, No.4 Printed in U.S.A .

EDITORIAL

The Immunopathogenesis of Dermatitis Herpetiformis

During the past two decades, the pace of research into t he pathogenes is of dermatitis herpetiformis (DH) has quickened. The first 80 yea rs after t he original description of DH by Duhring in 1884 [1] were marked by further characterization of t he clin ical di sease, an appreciation of the therapeutic value of sulfapyridine and su lfones in t he 1940s and 1950s (2], and accurate accounts of the hi stopathologic features of DH in 1890 [3] and again in t he early 1960s [4,5 ]. Since t he mid-1960s, three major observations have stimulated t he interest of inves­t igative dermatologists in this disease: (1) t he association of DH with specific histocompatibili ty antigens [6, 7], (2) t he description of a gluten-sensit ive enteropathy (GSE) in DH patients [8], and (3) the discovery of granular IgA deposits in t he skin of DH patients [9,10] . Although some of the pieces of t he puzzle relative to the immunopathogenes is of DH are now beginning to fall in to place, several cri t ica l aspects of the DH puzzle still must be solved.

Genetic susceptibility, an aspect of DH that is now becoming clear, is marked by an increased frequency of HLA types B-8, DR3, and a new OR-related antigen, Te24 [6,7,11]. T he strong associat ion with DR haplotypes implies that disease suscepti­b ility may be determined by specific immune response genes t hat are closely linked to t hese HLA ant igens. Those HLA types t hat occur with increased freq uency in DH are not specific fo r t his di sease but tend to be associated with other diseases w ith unusual immune reactivity, such as systemic lupus erythe­matosus, subacute cutaneous lupus erythematosus, sicca syn­drome, Graves' disease, and myasthenia gravis [1 2,13]. It ap­pears therefore that one component of t he genetic susceptibili ty to DH may be immu nologic hyperreactivity. In support of this hypothes is, other immunologically mediated diseases, including thyroid disease, lupus erythematosus, and atopy, may occur w ith increased frequency in patients with DH [14,15], and t here appears to be an unusual frequency in DH patients of certain autoantibodies including antit hyroid and antinuclear ant ibod­ies [16,17].

A second major piece of t he DH puzz le t hat seems secure is immunologic reactivity to dietary antigens, specifica lly to wheat protein ant ige ns. DH appears to occur in a subset of immuno­logically reactive individuals who a re predisposed to react to w heat prote in and to develop GSE. Facts supporting t his t hesis include t he occurrence of simila r HLA profiles in patients with symptomatic GSE and those with DH [6,7, 11], t he occurrence of symptomatic GSE and DH in t he same family and occasion­a lly in t he same individual [18,19], the presence of histo logic evidence of enteropathy, although often subt le, in most DH patients [8], the presence of circulating antibodies t hat react w ith wheat protein in bot h GSE and DH patients [20,21], and the response of both GSE and DH to a strict gluten-free diet [22,23]. Current t hinking is that reactiv ity to wheat protein is more t han a nonspecific phenomenon in DH and represents a critical factor in the genesis of t he skin disease.

The greatest difticul ty in understanding the pathogenes is of DH is in explaining how immune hyperreactivity and immune reactivi ty to wheat protein are related to t he t hird major discove ry, the deposition of granular IgA in the papillary dermis and along the basement membrane zone of t he sk in. The IgA deposit ion in DH skin is so distinctive and specifi c [24,25] that th is find ing must be centra l to t he evo lution of the inflamma­tory skin disease rather t han a nonspecific epiphenomenon. Evidence of t he potent ia l pathogenetic significance of t he IgA

237

deposits includes the presence of t he deposits in the uninvolved skin where t he rash ofDH may occur [9,10,25] and the presence along with the IgA deposits of complement components [25,26] which may lead to t he ingress and activation of neutrophils. A recent fascinating observation is t hat DH patients in remission on a strict gluten-free diet may lose t he IgA deposits in t he skin and that the IgA deposits return along with the clinical disease when a normal gluten-containing diet is resumed [27]. These observations point to t he cutaneous IgA deposits as t he crit ical link between sensit ivity to dietary wheat protei n and the inflammato ry skin disease.

To most investigators it has been plausible that the "DH factor ," that is, t he factor t hat determines the occurrence of skin disease in gluten-sensit ive individuals, is some abnormal­ity or immunopathogenetic mechanism which involves IgA [25,28). Several hypotheses have been proposed for the DH facto r. One study proposed that ant ibodies to small connective t issue fibers or reticulin may cross react with wheat protein (29). This findin g has not been confirmed, and there is litt le supporting evidence for the role of any IgA autoantibodies in the immu nopathogenesis of DH [28]. A second hypothesis is t hat circulating immune complexes involving IgA lead to t he cutaneous IgA deposits. In support of t his theory are positive Raji ce ll IgA immune complex assays of DH sera (28,30,31 ) and evidence t hat the reticuloendothelial system of DH pat ients may not clea r immune complexes in a normal manner (32]. However , the circulating immune complex t heory has not been total ly satisfactory: the granular IgA sta ining in DH skin is not in the blood vessels, as occurs with a circulating immune complex injury; histologic evidence of a vascular insult is usu­ally absent, both in t he skin and in other orga n systems; and pertinent ant igens, such as wheat protein antigens, have not been detected along with the IgA deposits [25,28). Another possibility that has not been t horoughly investigated is whether basic defects in IgA production and metabolism might exist in DH patients. Serum IgA levels tend to be elevated in DH [33,34] and specific IgA antibodies to gluten are elevated above those of GSE patients without DH [21]. No matter which hypothesis is being considered, however, the question t hat has never been adequately explained is why IgA, which may arise from the lymphoid t issue associated with the gastrointestinal t ract and respiratory t ract or from t he bone marrow, localizes in t he skin in DH.

In an attempt to better understand the cutaneous IgA depos­its of DH, many investigators have focused t heir research efforts on characterization of t hese deposits. By immunoelec­t ron microscopy, the IgA deposits are localized just beneath the basal lamina closely associated with fibri ll ar structures, which have been termed microfibrillary bundles [35-37]. By immu­nofluorescence staining, t he lgA deposits contain J chain whic h marks t he presence of at least some amount of dimeri~ lgA r3s]. In addition, the IgA is polyclonal and secretory component is absent [25,38].

A major hindrance to the study of the IgA deposits in DH sk in has been the inab ili ty of investigators to extract the IgA from DH skin biopsies. Katz and Strober [25] and other inves­tigators have noted the insolubil ity of these deposits. The first report that the IgA could be released from the skin deposits was t hat of Egelrud and Back in 1984 [39]. These researchers used a unique method fo r isolati ng small samples of papillary dermis and demonstrated that digestion by pepsin, but not by

238 EDITORIAL

trypsi n, collagenase, or elastase, caused a remarkable loss of t he IgA deposits, as detected by immunoflu orescence, and re­leased immunoreactive lgA into t he supernatant.

In t his issue of The Journal of Investigative Dermatology, t hese same authors have expanded their original observations and report extraction of IgA from DH skin by two methods, with t he detergent sodium dodecyl sulfate (SDS) and by pepsin digestion. By use of radio iodinated samples of papillary dermis, immunoprecipitation, and autoradiograp hy, t hey have demon­strated immunoreactive IgA in extracts of DH skin. The SDS­extracted IgA consisted of monomers, dimers, and high-molec­ular-weight polyme rs. The high-molecular-weight lgA material could not be eas ily degraded into smaller peptides and was thought to be irreversibly aggregated. Despite the use of ex­tremely sens it ive tech niques and a method of pepsin digestion that should preserve antigen-antibody bonds, t hese investiga­tors were unable to identify ant igens to which t he lgA might be bound. T he authors further suggest t hat t he effectiveness in release of lgA of pepsin digestion at pH 4.5, a technique that fragments t he Fe portion of immu noglobulin , may be compat­ible with the binding of t he lgA in the skin by the Fe portion of the mo lecule.

The implicat ions of th is work by Egelrud and Back fo r DH research are high ly significant. Now, for t he first t ime, the antige nic specificity of t he cutaneous lgA may be studied, and the binding of t he extracted lgA into DH and normal skin may be evaluated. T he techn iques described in t his paper wi ll be a sign ificant contribution to understanding of t he mechanism of l gA depos ition in the skin and may help to solve th is critical segment of the DH puzzle.

REFERENCES

J. Clark Huff, M.D. Un iversity of Colorado School of Medicine Denver, Colorado

I. Du hring LA: Dermatitis herpetiformi s. JAMA 3:225- 229, 1884 2. Lorincz AL, Pearson RW: Sulfapyridine and sulfone type drugs in

dermatology. Arch Dermatol 85:42- 56, 1962 3. Gi lchrest TC: T he pathology of a case of dermatitis herpetiformis

(Duh ring). J ohns Hopkins Hospital Reports 1:365- 371, 1890 4. Pierard J, Whimster l. The histological diagnosis of dermatitis

herpetiformis, bu llous pemphigoid, and erythema multi forme. Br J Dermatol 73:253- 266, 1961

5. McV icar ON, Graham JH , Burgoon CF: Dermatitis herpetiformis, erythema mul t ifo rme, and bullous pemph igoid: a comparative histopathological and histochemical study. J Invest Dermatol 41:289- 300, 1963

6. Katz Sl, Fa lchuk ZM, Dah l MY, Rogentine GW, Strober W: HL­A8: a genetic link between dermatitis herpetiformis and gluten sensitive enteropathy. J Clin Invest 51:2977-2980, 1972

7. Solheim BG, Ek J , T hune PO, Baklein K, Bratlir A, Rankin B, Thoresen AB, T horsby E: HLA antigens in dermatitis herpeti­form is and coeliac disease. ·fi ssue Antigens 7:57- 59, 1976

8. Marks J, Shuster S, Watson AJ: Small bowel changes in dermatitis herpetiformis. Lancet 2:1 280- 1282, 1966

9. Cormane RH: Immunofluorescent studies of t he skin in lupus erythematosus and other diseases. Pathologia Europ 2:170- 180, 1967

10. Van der Meer JB: Granular deposits of immunoglobulins in the skin of' patients with dermatitis herpetiformis. An immunoflu ­orescent study. Br J Dermatol 1:493- 503, 1969

11. Park MS, Terasaki PI, Ahmed AR, Zone J : The 90% incidence of HLA antigen (Te24) in dermatitis herpetiformis. Tissue Antigen 22:263- 266, 1983

12. Ryder LP, Svejgaard A: Genetics of HLA disease association. Annu Rev Genet 15:169- 187, 1981

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13. Sontheimer RD, Maddison PJ, Reichlin M, Jordon RE, Stastny P , Gilliam JN: Serologic and HLA associations in subacute cuta­neous lupus erythematosus, a clinical subset of lupus erythema­tosus. Ann Inte rn Med 97:664-671, 1982

14. Scott BB, Lasowsky MS: Coeliac disease: a cause of various asso­ciated diseases. Lancet 2:956-957, 1975

15. Davies MG, Marks R, Nuki G: Dermatitis herpetiformis: a skin manifestation of a generalized disturbance of immunity. Q J Med 47:221-248, 1978

16. Fraser NG: Autoantibodies in dermatitis herpetiformis. Br J Der­matol 83:609-613, 1970

17. Seah PP, Fry L, Hoffbrand AV, Holborow EJ: T issue ant ibodies in dermatitis herpetiform is and adult coeliac disease. Lancet 1:834-836, 1971

18. Walker-Smith JA, Talley NA: Coeliac disease and dermatitis her­petiformis. Med J Aust 1:10-12, 1973

19. Reunala T, Salo OP, Tiilikainen A, Silroor 0, Kartunen P: Family studies in dermatitis herpetiform is. Ann Clin Res 8:254-261 , 1976

20. Huff JC, Weston WL, Zirker OK: Wheat protein antibodies in dermatit is herpeti formis. J Invest Dermatol 73:570-574, 1979

21. Lane AT, Huff JC, Zone JJ, Weston WL: Class-specific antibodies to glu ten in dermatitis herpetiformis. J Invest Dermatol 80:402-405, 1983

22. Fry L, McMinn RMH, Cowan J , Hoffbrand AV: Effect of gluten­free diet on dermatological, in testinal and hematological mani­festations of dermatitis herpetiformis. Lancet 1:557- 561, 1968

23. Fry L, Seah PP, Riches DJ, Hoffbrand AV: Clearance of skin lesions in dermatitis herpetiform is after gluten withdrawal. Lan­cet 1:288-291, 1973

24. Fry L, Seah PP: Cri te ria for the diagnosis of dermatitis herpetifor­mis. Proc R Soc Med 66:43- 44, 1973

25. Katz SI, Strober W: T he pathogenesis of dermatitis herpetiform is. J Invest Dermatol 70:63-75, 1978

26. P rovost TT, Tomasi TB: Evidence fo r the activation of comple­ment via the alte rnate pathway in sk in diseases. ll . Dermatitis herpetiformis. Clin lmmunol Immunopathol 3:178-186, 1974

27. Leonard J, Hoffenden G, Tucker W, Unsworth J , Swain F, McMinn R, Holborow J, Fry L: Gluten challenge in dermatitis herpetifor­mis. N Eng! J Med 308:816- 819, 1983

28. Katz SI, Hall RP, Lawley TJ, Strober W: Dermatitis herpetiformis: the skin and the gut. Ann Intern Med 93:857-874, 1980

29. Seah PP, Fry L, Stewart JS, Chapman BL, Hoffbrand AV, Hol­borow EJ: Immunoglobulins in the skin in dermatitis herpetifor­mis and coeliac disease. Lancet 1:611- 614, 1972

30. Zone JJ, LaSalle BA, Provost TT: Circulating immune complexes of lgA type in dermatitis herpetiformis. J Invest Dermatol 75:152- 155, 1980

31. H all RP, Lawley TJ, Heck JA, Katz Sl: lgA containing circulating immune complexes in dermatitis herpetiformis, Henoch-Schoen­lein purpura, systemic lupus erythematosus and other diseases. Clin Exp Immunol 40:431-437, 1980

32. Lawley TJ, Hall RD, Fauci AS, Katz Sl, Hamburger MI, Frank MM: Defective Fc-receptor functions associated with the HLA­B8/DRW3 haplotype: studies in patients with dermatitis her­petiformis and normal subjects. N Eng! J Med 304:185- 192, 1981

33. Fraser NG, Dick HM, Crichton WB: Immunoglobulins in derma­t itis herpetiformis and various other skin diseases. Br J Dermatol 81:89- 95, 1969

34. McClelland DBL, Barnetson R St.C, Parkin OM, Warwick RRG, Heading RC, Shearman DJC: Small intestinal immunoglobulin levels in dermatitis herpetiformis. Lancet 2: 1108- 1110, 1972

35. Sting! G, Hiinigsmann H, Holubar K, Wolff K: Ult rastructural localization of immunoglobulins in dermatitis herpetiformis. J Invest Dermatol 67:507-512, 1976

36. Y aoita H, Katz SI: Immunoelectronmicroscopic localization of lgA in skin of patients with dermatitis herpetiform is. J Invest Der­matol 67:502-506, 1976

37. Yaoita H: Ident ification of IgA binding structures in skin of pa­t ients with dermatitis herpetiformis. J Invest Dermatol 71 :213-216, 1978

38. Unsworth OJ, Payne AW, Leonard JN, Fry L, Holborow EJ: lgA in dermatitis herpetifo rmis skin is dimeric. Lancet 1:478-480, 1982

39. Egelrud T, Back 0: Dermatitis herpetiformis: preparation of pap­illa ry dermis and the effect of proteolytic enzymes on the IgA deposits. J Invest Dermatol 82:501-505, 1984