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antinuclear antibodies of the skin: A rare phenomenon on direct immunofluorescence

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In vivo antinuclear antibodies of the skin: A rare phenomenon on direct immunofluorescence
Seema Chhabra MD, Sandeep Kumar Arora MD, Ranjana Walker Minz MD, Suneel Dogra MD
Dermatology Online Journal 19 (4): 15

PGIMER, Chandigarh, UT, India


Detection of immunoglobulins in epidermal cell nuclei or in vivo antinuclear antibodies on direct immunoflorescence microscopy of skin biopsies is an easily detectable immunopathologic feature. It is an unusual, but not totally rare, occurrence in systemic connective tissue disorders. This positive epidermal nuclear reaction is found to be commonly associated with immunoglobulin G.


Figure 1

Antibodies to nuclei of epidermal cells are found in patients with various systemic connective tissue disorders (SCTDs). The study was undertaken with an aim to analyze the prevalence of in vivo antinuclear antibody phenomenon or positive epidermal nuclear staining (ENS) on direct immunofluorescence (DIF) microscopy of skin biopsy specimens from patients with various SCTDs and other related disorders. Additionally, the presence of ENS was correlated its existence with anti-nuclear antibodies (ANA) in the serum (Figure 1).

Materials and Methods

In this retrospective study, a total of 52 cases (3% of all biopsies submitted in the 10 year period 1999-2008) showing ANA in vivo on DIF of skin biopsies were retrieved from records of the department. The clinical data were collected and the same was recorded along with histopathological diagnosis and serum ANA test results. The pattern of ENS staining was not recorded.


Out of these 52 patients, 48 presented with a clinical diagnosis of SCTDs. The diagnostic distribution, details of DIF results of skin biopsy, and serum ANA test results are shown in Table 1. SLE was the most common disorder (20 cases) showing positive ENS. Nuclear keratinocyte decoration has seen along with various patterns on DIF like lupus band test, civatte bodies, and superficial blood vessel staining. ENS was found to be positive; immunoglobulin (Ig) G was the most common immunoreactant (34/48 cases) with evidence of complement activation (C3 positivity) in 5 cases. Serum ANA test results were available in 28/48 cases wherein ANA was positive in 20 cases and negative in eight cases (Table 1). Because the pattern of ENS was not identified and serum ANA test results were available in only half of the patients; no correlation was found between ANA in vivo pattern and the serum ANA positivity as well as morphologic pattern. In addition, four cases that included clinically and immuno-histopathologically proven disorders, two cases of pemphigus vulgaris (PV) and two cases of bullous pemphigoid (BP), also showed positive ENS. Serum ANA test was not performed in these cases.


Epidermal nuclear fluorescence is a true reaction in vivo between antinuclear antibodies to certain specificities (i.e., anti-ribonucleoprotein antibodies) and epidermal cell nuclei [1]. In addition, there are certain other permeability enhancing co-factors that permit penetration of ANAs across cell membrane barriers [2]. However, we have also observed this phenomenon in eight patients with SCTDs in which serum ANA was negative. McCoy et al have also noted the persistence of ENS even when serum antibodies were negative [3].

This study has identified IgG as the main immunoglobulin involved in epidermal nuclear reaction, in line with the previous studies [1, 2, 4]. Also complement activity is noted in five cases which is contrary to the results of Izuno [4]. We have also observed ENS in two patients with PV and two patients with BP. Grunwald et al have reported the IgG deposition in epidermal nuclei in a patient with PV along with positive ANA in the serum and regarded it as a phenomenon of “autoimmunity” [5]. Blondin et al have detected ANA positivity in serum specimens in 37 percent of PV patients and suggested it to be a manifestation of a subclinical form of a SCTD in the same patients [6].

Thus, the appearance of epidermal nuclear fluorescence is an unusual, but not totally rare, occurrence. The patients suffering from autoimmune blistering diseases of the skin showing ENS on skin biopsy should be screened for signs and symptoms of other SCTDs to determine its prognostic and therapeutic significance.


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2. Rao R, Balachandran C. Epidermal nuclear staining: A distinct reaction pattern in connective tissue diseases. Indian J Dermatol Venereol and Leprol 2007;73:120-12. [PubMed]

3. McCoy RC. Nuclear localization of immunoglobulin in renal biopsies of patients with lupus nephritis. Am J Pathol 1972;68:469-78. [PubMed]

4. Izuno GT. Observations on the in vivo reaction of antinuclear antibodies with epidermal cells. Br J Dermatol 1978;98:391-98. [PubMed]

5. Grunwald MH, David M, Ginzburg A, Feuerman EJ. Pemphigus vulgaris with a high titre of antinuclear antibodies. Arch Dermatol 1984; 120:996. [PubMed]

6. Blondin DA, Zhang Z, Shideler KK, Hou H, Fritzler MJ, Mydlarski PR. Prevalence of non-organ-specific autoantibodies in patients with pemphigus vulgaris. J Cutan Med Surg 2009;13:82-7. [PubMed]

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