Review Article

Desmoglein Compensation Theory: An explanations for Early Appearance of Oral lesions as Compared to Skin Lesions in Vulgaris

1* 2 3 4 Safia Siddiqui , Mohammad Asad Haroon , Shamim ul Hasan , Aeman Khalid 1Department of Oral Pathology and Microbiology, Sardar Patel Post Graduate Institute of Dental & Medical Sciences, Lucknow- 226025 (U.P.), 2Assistant Professor, Department of Dermatology, Integral Institute Medical Sciences and Research, Lucknow, 3Assistant Professor, Department of Oral Medicine and Radiology, Faculty of Dentistry, Jamia Milia Islamia, New Delhi, 4Post Graduate Student (MD pathology), Jawaharlal Nehru Medical College, AMU, Aligarh

ABSTRACT

Pemphigus is a life-threatening autoimmune blistering disease targeting skin and mucous membranes. It is clinically characterized by flaccid blisters and erosions, while histologically shows intraepithelial acantholysis. The disruption of desmoglein-dependent by autoantibodies is the basic pathophysiology in blister formation of pemphigus. The clinical and histological spectrum of pemphigus is complex and differs in various variants of pemphigus. This review offers an answer to why the splits associated with pemphigus foliaceus occur in the superficial layer of the epidermis, while those of occur deep in the epidermis. With the help of desmoglein compensation theory, it logically explains why oral erosions develop in patients with pemphigus vulgaris, but not in patients with pemphigus foliaceus and why some patients with pemphigus vulgaris have only oral involvement, but others have extensive lesions on both skin and mucous membranes. Learning objective: After completing this article, readers shall be familiar with the clinical presentations, histologic findings, immunopathology of classical pemphigus and its variants. It discusses the desmoglein compensation theory of pathogenesis. along with the management of pemphigus.

Key words: Pemphigus, Desmoglein Compensation Theory, Autoimmune disorder, Blister

INTRODUCTION

The term Pemphigus stems from the Greek word Pemphix originally named by Wickham in 1791.(3) The modern (bubble or blister).(1) It is a group of potentially life- history of Pemphigus began with the discovery of threatening autoimmune diseases characterized by circulating antibodies directed against the cell surface of cutaneous and mucosal blistering.(2) Pemphigus was keratinocytes in the sera of Pemphigus Vulgaris patients by Beutner and Jordon in 1964.(4) It affects 0.1-0.5 patients per Access this article online 100,000 population per year.(5) Oral lesions of pemphigus Website: Quick Response code are seen in up to 18% of patients at dermatology out-patient www.iabcr.org (6) DOI: clinics. The prevalence of Pemphigus is equal in both 10.21276/iabcr.2016.2.3.3 men and women. The mean age of onset is 50-60 yrs.(3) Certain ethnic groups, such as Ashkenazi Jews and those of Received:25.06.16| Revised:12.07.16| Accepted:15.07.16 (7) Mediterranean origin, are especially liable to pemphigus. Corresponding Author There is a fairly strong genetic background to pemphigus Dr. Safia Siddiqui, MDS (Oral Pathology & Microbiology), Senior Lecturer, Department of Oral Pathology and with linkage to HLA class II alleles. The three primary Microbiology, Sardar Patel Post Graduate Institute of Dental & subsets of Pemphigus include Pemphigus vulgaris (PV), Medical Sciences, Lucknow- 226025 (U.P.) Pemphigus Folaceous and . Each Copyright: © the author(s) and publisher. IABCR is an official publication of Ibn Sina Academy of Medieval Medicine & Sciences, registered in 2001 type has distinct clinical and immunopathological (3) under Indian Trusts Act, 1882. This is an open access article distributed features. However Pemphigus vulgaris accounts for under the terms of the Creative Commons Attribution Non-commercial License, which permits unrestricted non-commercial use, distribution, and approximately 70% of Pemphigus cases. These three reproduction in any medium, provided the original work is properly cited. Pemphigus has been reviewed in the oral literature,(8),(9) but

www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3 13 | Page

Siddiqui S, et al.: Desmoglein Compensation Theory

several advances in the understanding of the Fogo selvagem etiopathogenesis, pemphigus variants, and management It is clinically, histologically, immunopathologically warrant an update. similar to Pemphigus Foliacieus. It occurs in endemic fashion in certain regions of Brazil. Effects young adults Classification of Pemphigus and children. There is a high frequency of Hematophagous (1) Pemphigus is classified as bugs in the homes of patients with fogo selvagem. (1) § Pemphigus vulgaris Pemphigus vegetans Herpetiform Pemphigus Pemphigus foliaceus Pemphigus herpetiformis is recognized as a distinct variant Pemphigus erythematous: localized of pemphigus by its pruritus, the invariable presence of Fogo selvagem: endemic eosinophils and/or neutrophils, and its tendency to respond § Herpetiform Pemphigus to sulfones. Occasional oral lesions are also present. (13) § Drug induced Pemphigus Drug Induced Pemphigus § Paraneoplastic Pemphigus Penicillamine and Captopril contain sulfahydryl groups § IgA Pemphigus which modify the desmoglein, leading to defect in their

Variants of Pemphigus adhesive functions. In some patients sporadic cases of (1) Pemphigus Vulgaris Pemphigus are seen with the use of these drugs.

It is the most common variant of Pemphigus. PV is divided Paraneoplastic Pemphigus into two subgroups Recently Paraneoplastic Pemphigus is recognised as a a. Mucosal dominant type with mucosal erosions but disease distinct with classic form of Pemphigus. Patient has minimal skin involvement a known or occult neoplasm which could be malignant or b.Mucocutaneous type with extensive skin blisters and benign. The most commonly associated neoplasms are erosions in addition to mucosal involvement. Mucous Non-Hodgkin’s Lymphoma. (1) The most observed clinical membrane lesions usually present with painful erosions feature of paraneoplastic pemphigus is an intractable of the oral mucosa but intact blisters are rare. Skin lesions stomatitis, which is usually the earliest presenting sign, and [1] are flaccid thin walled blisters. These blisters easily is extremely resistant to therapy.(14) The stomatitis consists (10) rupture and leave patients susceptible to infection. of painful erosions and ulcerations of the oropharynx and Nikolsky’s sign, ‘Bulla Spread phenomenon’ (Asboe vermilion borders of the lips.(14),(15) Most patients also have Hansen sign also referred to Indirect Nikolsky or a severe pseudomembranous conjunctivitis.(15) Nikolsky II sign) can be demonstrated. High number of patients with PV may present with active ENT lesions, IgA Pemphigus furthermore patients with ear, nose and throat IgA Pemphigus is a recently recognised group of involvement may be asymptomatic.(11) autoimmune intra-epidermal blistering disease. It is characterised by vesiculopustular eruptions, neutrophilic Pemphigus Vegetans infiltration of skin and IgA autoantibodies against cell It is characterised by flaccid blisters that become erosions (1) surface keratinocytes. Mucosal involvement is rare. and then form papillomatous proliferations or fungoid There are two distinct types of IgA pemphigus: the vegetations especially in the intertriginous areas and face. subcorneal pustular dermatosis (SPD) type and the intra- Tongue show cribriform like changes. Two subtypes are epidermal neutrophilic (IEN) type, also referred to as “IgA recognized: the severe Neumann type and the mild (1) pemphigus foliaceus” and “IgA pemphigus vulgaris,” Hallopeau type. (16), (17) respectively.

Pemphigus Foliaceus Etiopathogenesis Patients develop scaly, crusted cutaneous erosions An elementary knowledge of the biology of the oral resembling “corn flakes”, but do not have mucosal is crucial to the understanding of pemphigus. involvement even with widespread disease. In contrast to The oral epithelium is a complex structure consisting of a (1) PV extensive oral lesions are extremely rare. There are a range of cells, mainly keratinocytes, adherent to each other number of studies showing pemphigus features with by . Desmosomes are adhesion proteins of the clinical shifting between PF and PV and vice versa. Their family that contain a series of proteins, results showed that the transition between PF and PV particularly desmogleins (Dsg) and .(7),(18) correlates well with a serologic switch from antibodies Desmogleins are the principal target of PV autoantibodies: against Dsg1, typical of PF, to antibodies against Dsg3, (19),(20) Desmogleins (Dsgs) are thought to be synthesized as (12) which are a marker of PV. inactive precursor proteins and are cleaved by convertases (21) Pemphigus Erythemotous (Senear Usher Syndrome) to yield mature adhesive molecules. Desmogleins have It is a localised variant of Pemphigus Foliceus. Typical four isoforms (Dsg 1-4). Dsg1 and Dsg3 are the main scaly and crusted lesions of Pemphigus Foliaceus appear on adhesion glycoproteins in the stratified squamous epithelia, the malar region of the face. (1) they are coexpressed, and have a synergic role in the maintenance of epithelial integrity.(22) www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3 14 | Page

Siddiqui S, et al.: Desmoglein Compensation Theory

Intraepithelial expression pattern of Dsg 1 and Dsg 3 differ major cause of the acantholytic cleft in pemphigus, then between skin and mucous membrane. In the skin Dsg 1 is binding of autoantibodies to either Dsg1 or Dsg3 would expressed throughout the epidermis, but more intensely in cause protease release and blister formation and prevent the superficial layers where as Dsg 3 is expressed only in functional compensation of one by the other.(32) the deeper epidermis i.e, in the basal and immediate The assumption that anti-Dsg3/Dsg1 autoantibodies are suprabasal layer.(1,18) In contrast to the skin , both Dsg 1 and sufficient to cause blisters in patients with PV ad PF raises Dsg3 are expressed throughout the mucosal epithelium, a series of questions: (i) Why would PV patients however Dsg 1 is expressed in a much lesser amount than harbouring both Dsg1 and Dsg3 antibodies develop only Dsg 3. (22) suprabasilar rather than suprabasilar and subcorneal blisters? (ii) Why does Dsg1 antibody not cause a granular DISCUSSION layer split in PV? (iii) Why do some people who have Desmoglein Compensation Theory circulating anti-Dsg1 and/or Dsg3 antibodies not manifest Dsg1 and Dsg3 compensate their adhesive function when pemphigus?(33) co-expressed on the same cell. (23), (24), (25) It has been suggested that the distribution and expression levels of Dsg1 and Dsg3 might account for the characteristic blisters’ distribution and localization in PV and PF patients.(23) It is known that Dsg 3 is expressed throughout the oral mucosa, especially in the upper two-thirds, whereas in the epidermis it is expressed only in the basal and immediate suprabasal layers.(22) Conversely, Dsg1 is expressed throughout the epidermis and oral mucosa but more intensely in the subcorneal layer and very weakly in the deep epidermis (26) (Fig 1: A1,B1). The clinical phenotype of pemphigus is defined by the antidesmoglein autoantibody profile.(27) Some patients with PV have only anti-Dsg3 IgG, whereas other PV patients have both anti-Dsg3 and anti-Dsg1 IgG. Patients with PF have only anti-Dsg1 IgG.(27),(28),(29) On the basis of the above findings, and speculating that Dsg1 and Dsg3 compensate their adhesive function when co-expressed on the same cell, the localization of blister formation in pemphigus can very well be explained. In fact, PF anti-Dsg1 IgG causes blisters in the superficial layers of the epidermis but not in the deep epidermis or mucosa, where the expression of Dsg3 compensates for the antibody-induced functional loss of Dsg1 (Fig 1: A1,B1). Similarly, in Mucosal PV, anti-Dsg3 IgG causes acantholysis in the deepest layers of the mucous membranes where Dsg1 expression is minimal but not in the skin where epidermal integrity is guaranteed by the Fig 1. Explanation of localization of vesicle formation in classic pemphigus by desmoglein compensation theory. The high expressivity of Dsg1 (Fig. 1: A2, B2).(25),(30) Hence in coloured triangles represent the distribution of desmoglein Mucosal dominant Pemphigus Vulgaris only oral erosions (Dsg 1) and desmoglein 3(Dsg 3) in the skin and mucous (1) are seen without apparent skin involvement. membrane. Pemphigus folaceous sera contain only anti Dsg Moreover, in Mucocutaneous PV, both anti-Dsg1 and anti- 1 , which causes superficial blisters in the skin because Dsg3 Dsg3 antibodies are present, hence in the epidermis ‘low functionally compensates for the impaired Dsg 1 in the lower acantholysis’ occurs as well (Fig 1: A3, B3). It is not clear part of the epidermis (A 1), whereas those antibodies do not cause blisters in the mucous membranes because cell-cell that why the split occurs just above the basal layer instead adhesion is mainly mediated by Dsg3( B1). Sera containing of the whole epithelium falling apart. However it is only anti –Dsg 3 IgG causes no or only limited blisters in the speculated that the cell–cell adhesion between the basal and skin because Dsg 1 compensates for the loss of Dsg 3 the immediate suprabasal layers might be weaker than the mediated adhesion (A 2) ; however, these sera induce other parts of the epidermis, because there are fewer separation in the mucous membranes, where the low desmosomes. In addition, the lower part of the epidermis expression of Dsg 1 will not compensate for the loss of Dsg3 might have better access for autoantibodies which penetrate mediated adhesion (B2). When sera contains both anti Dsg 1 and anti Dsg3 IgG, the function of both Dsgs is compromised from the dermis. That may explain why the splits become (1), ( 31) and blisters occur in both the skin and mucous membranes ( suprabasilar in Mucocutaneous PV. However, this A 3 and B 3) . In neonatal skin, the situation is similar to that Dsg compensation theory is incompatible with the protease shown here for mucous membranes. theory of blister formation, because if plasmin was the www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3 15 | Page

Siddiqui S, et al.: Desmoglein Compensation Theory

and enzyme-linked immunosorbent assay (ELISA). (7). (41) Recently Dsg 1 and 3 antigen specific ELISA has been introduced in which the ELISA plates are precoated with these antigens.(1)

Histological Features The characteristic histological finding in Pemphigus Vulgaris is Intraepidermal blister formation due to suprabasilar acantholysis with no keratinocytic necrosis. The basal cells lose their lateral attachment but maintain their attachment with the basement membrane thus giving the appearance of “row of tombstone.” The blister cavity may contain few rounded up keratinocytes along with few inflammatory cells, notably eosinophils. In the dermis there

Fig 2. Flowchart explaining the various mechanisms in the is moderate perivascular infiltrate with conspicuous genesis of acantholysis (blister formation) in Pemphigus eosinophils. In some cases the earliest histological finding consist of eosinophilic spongiosis, in which eosinophils Today multiple classes of targets are considered to play a invade spongiotic epidermis with no evidence of role in the genesis of the acantholysis. Among these, the acantholysis.(1) classical pemphigus antigens, desmosomal (Dsg In Pemphigus foliaceous, Pemphigus Erythematous and 1 & 3) are the best characterized and considered as the fogo selvagem acantholysis occur in upper epidermis, most important. Additional antigens include the novel blisters are fragile. In Paraneoplastic Pemphigus, (34) epithelial acetylcholine receptors (α9 and pemphaxin). keratinocytic necrosis, basal cell liquefactive degeneration The various proposed mechanism by which the formation with band like lymphocytic infiltrate in the upper epidermis of blister takes place in Pemphigus are shown in the form is seen. Eosinophils are rare. In IgA pemphigus (1), (34) of a flowchart (Fig 2). neutrophilic intraepidermal pustule is seen with no Thus, acantholysis in pemphigus seems to result from a acantholysis.(1) cooperative action of antibodies to different keratinocyte self-antigens, but the mechanisms by which epithelial cleft Treatment occurs are not yet clearly understood. In fact, the binding of Current treatment is largely based on systemic the autoantibodies to these targets generates a plethora of immunosuppression using systemic corticosteroids, biological effects due, on one hand, to their direct azathioprine, dapsone, methotrexate, cyclophosphamide, interference with adhesive function and, on the other, to and gold as adjuvants or alternatives.(7) Plasmapheresis is more complex events involving intracellular pathways that useful in reducing the titre of circulating autoantibodies in modify proteases activity or calcium metabolism, leading to severe Pemphigus.(1) More recently, high-dose intravenous (34) loss of cell–cell adhesion. immunoglobulins, immune adsorption, and the monoclonal anti-CD20 antibody, rituximab, have been established as Diagnosis additional successful therapeutic options.(38) Rituximab The clinical diagnosis of PV can be confirmed in several belongs to the class of biologicals and is a specific mouse ways: histologic findings of suprabasal acantholysis, direct and human chimeric monoclonal antibody. This IgG1 has a immunofluorescence (DIF) showing intercellular deposits long half-life of 76 to 200 h and targets the CD20 antigen. of IgG and C3, and evidence of circulating antibodies by The CD 20 antigen is present on pre-B, immature and indirect immunofluorescence (IIF) or enzyme-linked mature B cells and is important for B-cell activation and (10) immunosorbent assay. Tzanck smear is generally used proliferation. Binding of rituximab to CD 20 results in for the diagnosis of the pemphigus group of complement- and antibody-dependent cytotoxicity and (35) autoimmunobullous diseases. Positivity of acantholytic subsequent apoptosis of cells exhibiting this antigen. (39) cells in Tzanck smear test in cases with pemphigus has Mycophenolate mofetil (MMF) also appear promising.(7) (36) been reported between 93.3% and 100%.

In addition to typical acantholytic cells, Sertoli rosette cells REFERENCES

(consists of cell aggregates with an epithelial cell at the rd 1. BOLOGNIA J L, JORIZZO J L, SCHAFFER J V. Dermatology. 3 center surrounded by a ring of leukocytes) and streptocytes edition. Vol 1. Saunders Elseviers, New Delhi; 2012: 461- 473. (chains of white blood cells) may also be observed in cases 2. SCULLY C, CHALLACOMBE S J. PEMPHIGUS VULGARIS: (37) Update on Etiopathogenesis, Oral Manifestations And of pemphigus. Management. Crit Rev Oral Biol Med 2002; 13(5): 397-408. Biopsy of perilesional tissue, with histological and 3. RAJENDRAN R, SIVAPATHASUNDARAM. Shafer's textbook of immunostaining examinations, is essential to the diagnosis. oral pathology. New Delhi: Elsevier, 2012: 824-828. 4. BEUTNER EH, JORDON RE. Demonstration of skin antibodies in Detection of serum autoantibodies to either Dsg1 or Dsg3 sera of Pemphigus vulgaris patients by indirect immunoflourescent are the gold standard. They can be detected by direct or staining. Proc Soc Exp Biol Med1964; 117: 505-10. indirect flouresence, immunoprecipitation, immunoblotting

www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3 16 | Page

Siddiqui S, et al.: Desmoglein Compensation Theory

5. BECKER BA, GASPARI AA. Pemphigus vulgaris and vegetans. 24. STANLEY JR, AMAGAI M. Pemphigus Bullous Impetigo and Dermatol Clin 1993; 11:429-453. the staphylococcal scalded skin syndrome. N Engl J Med. 2006; 6. RAMIREZ-AMADOR VA, ESQUIVEL-PEDRAZA L, 355: 1800-10. OROZCO-TOPETE R. Frequency of oral conditions in a 25. PAYNE AS, HANAKAWA Y, AMAGAI M, STANLEY JR. dermatology clinic. Int J Dermatol 2000; 39: 501-505. Desmosomes and disease: pemphigus and bullous impetigo. Curr 7. GROVES RW. Pemphigus: a brief review. Clinical Medicine Opin Cell Biol 2004; 16: 536. 2009; 9 (4):371–5. 26. JONES JCR, YOKOO KM, GOLDMAN R. Further analysis of 8. EVERSOLE LR. Immunopathology of oral mucosal ulcerative, pemphigus autoantibodies and their use in studies on the desquamative and bullous diseases. Selective review of the heterogeneity, structure and function of desmosomes. J Cell Biol literature. Oral Surg Oral Med Oral Pathol 1994; 77: 555-571. 1986; 102: 1109. 9. WEINBERG MA, INSLER MS, CAMPEN RB. Mucocutaneous 27. AMAGAI M, TSUNODA K, ZILLIKENS D, NAGAI T, features of autoimmune blistering diseases. Oral Surg Oral Med NISHIKAWA T. The clinical phenotype of pemphigus is defined Oral Pathol Oral Radiol Endod 1997; 84: 517-534. by the antidesmoglein autoantibody profile. J Am Acad 10. HARMAN KE, ALBERT S, BLACK MM. British Association of Dermatol 1999; 40: 167. Dermatologists. Guidelines for the management of pemphigus 28. DING X, AOKI V, MASCARO` JM, LOPEZ-SWIDERSKI A, vulgaris. Br J Dermatol 2003;149:926-37. DIAZ LA, FAIRLEY LA. Mucosal and mucocutaneous 11. KAVALA M, ALTINTAS S, KOCATURK E, ZINDANCI I, (generalized) pemphigus vulgaris show distinct autoantibody CAN B, RUHI C, TURKOGLU Z. Ear, nose and throat profiles. J Invest Dermatol 1997; 109: 592. involvement in patients with pemphigus vulgaris: correlation with 29. NAGASAKA T, NISHIFUJI K, OTA T, WHITTOCK NV, severity, phenotype and disease activity. JEADV 2011; 25: 1324– AMAGAI M. Defining the pathogenic involvement of desmoglein 1327. 4 in pemphigus and staphylococcal scaled skin syndrome. J Clin 12. The clinical transition between pemphigus foliaceus and Invest. 2004; 114: 1484. pemphigus vulgaris correlates well with the changes in 30. TSUNODA K, OTA T, AOKI M, YAMADA T, NAGAI T, autoantibody profile assessed by an enzyme-linked NAKAGAWA T, KOYASU S et al. Induction of pemphigus immunosorbent assay. Br J Dermatol 2001; 144(6): 1177- 1182. phenotype by a mouse monoclonal antibody against the 13. ROBINSON ND, HASHIMOTO T, AMAGAI M, CHAN LS. The aminoterminal adhesive interface of desmoglein 3. J Immunol new pemphigus variants. J Am Acad Dermatol. 1999; 40: 649– 2003; 170: 2170. 671. 31. AMAGAI M. Autoimmunity against desmosomal cadherins in 14. ANHALT GJ. Paraneoplastic pemphigus. Adv Dermatol pemphigus. J Dermatol Sci 1999; 20: 92. 1997;12:77-96. 32. UDEY MC, STANLEY JR. Pemphigus – diseases of 15. ANHALT GJ, KIM S, STANLEY JR, KORMAN NJ, JABS DA, antidesmosomal autoimmunity. JAMA 1999; 282: 572. KORY M, IZUMI H, et al. Paraneoplastic Pemphigus. An 33. GRANDO SA, PITTELKOW MR, SHULTZ LD, autoimmune mucocutaneous disease associated with neoplasia. N DMOCHOWSKI M, NGUYEN VT. Pemphigus: an unfolding Eng J Med. 1990; 323: 1729-35. story. J Invest Dermatol 2001; 117: 990. 16. BEUTNER EH, CHORZELSKI TP, WILSON RM, KUMAR V, 34. LANZA A, CIRILLO N, FEMIANO F, GOMBOS F. How does MICHEL B, HELM F, JABLONSKA S. IgA pemphigus foliaceus: acantholysis occur in pemphigus vulgaris: a critical review. J report of two cases and a review of the literature. J Am Acad Cutan Pathol 2006; 33: 401–412. Dermatol 1989; 20:89-97. 35. DURDU M, BABA M, SECKIN D. The value of Tzanck smear 17. EBIHARA T, HASHIMOTO T, IWATSUKI K,TAKIGAWA M, test in diagnosis of erosive, vesicular, bullous, and pustular skin ANDO M, OHKAWARA A, NISHIKAWA T . Autoantigens for lesions, J Am Acad Dermatol. 2008; 59( 6): 2008 958-964. IgA anti-intercellular antibodies of intercellular IgA 36. BLANK H, BURGOON CF. Abnormal cytology of epithelial cells vesiculopustular dermatosis. J Invest Dermatol 1991;97:742-5. in pemphigus vulgaris: a diagnostic aid. J Invest Dermatol 1952; 18. AMAGAI M, KOCH P J, NISHIKAWA T, STANLEY JR. 18:213-23. . Pemphigus Vulgaris antigen (Desmoglein 3) is localized in the 37. GUPTA LK, SINGHI MK. Tzanck smear: a useful diagnostic tool. lower epidermis, the site of blister formation in patients. J Invest Indian J Dermatol Venereol Leprol 2005;71: 295-9. Dermatol.1996; 106: 351–355. 38. KASPERKIEWICZ M, SCHMIDT E, ZILLIKENS D. Current 19. AMAGAI M, HASHIMOTO T, SHIMIZU N, NISHIKAWA T. therapy of the pemphigus group. Clinics in Dermatology. 2012; Absorption of pathogenic autoantibodies by the extracellular 30: 84–94. domain of pemphigus vulgaris antigen (Dsg3) produced by 39. SUNDHARAM J. Anti-CD20 monoclonal antibody (rituximab) in baculovirus. J Clin Invest 1994; 94: 59. the treatment of pemphigus. Indian J Dermatol Venereol Leprol 20. GETSIOS S, HUEN AC, GREEN KJ. Working out the strength 2006; 72:173-4. and flexibility of desmosomes. Nat Rev Mol Cell Biol 2004; 5: 40. TOTH GG, JONKMAN M F. Therapy of Pemphigus. Clinics in 271. Dermatology 2001;19: 761–767. 21. YOKOUCHI M, SALEH MA, KURODA K, HACHIYA T, 41. HASHIMOTO T. Recent advances in the study of the STANLEY JR, AMAGAI M, ISHII K. Pathogenic epitopes in pathophysiology of pemphigus. Arch Dermatol Res A 2003; pemphigus unmasked by proteolysis. J Inv Dermatol 2009; 129: Apr;295 Suppl 1:S2-11.

2156-2166. 22. SHIRAKATA Y, AMAGAI M, HANAKAWA Y, NISHIKAWA How to cite this article: Siddiqui S, Haroon MA, Hasan S, Khalid A. T, HASHIMOTO K. Lack of mucosal involvement in Pemphigus To Determine Desmoglein Compensation Theory: An explanation for Foliceous may be due to low expression of desmoglein 1. J Invest early appearance of oral lesions as compared to skin lesions in Dermatol. 1998; 110: 76-8. Pemphigus vulgaris. Int Arch BioMed Clin Res. 2016;2(3):13-17. DOI: 23. MAHONEY MG, WANG Z, ROTHENBERGER K, KOCH PJ, 10.21276/iabcr.2016.2.3.3 AMAGAI M, STANLEY JR. Explanation for the clinical and

microscopic localisation of lesions in Pemphigus foliceus and Source of Support: Nil, Conflict of Interest: None vulgaris. J Clin Invest.1999; 103: 461-8.

www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3 17 | Page