Anti-neuronal IgG Antibodies in Bullous Pemphigoid Coexistent with Neurodegeneration.

Sir,

Previously, epidemiological data from a national registry indicated the association between bullous pemphigoid (BP) [Figure 1] and neurodegenerative disorders (ND).[1] BP antigens exist also in their neurological isoforms located in the central nervous system. Certain studies[2] directly linked ND and BP through an antibody-based mechanism.

Figure 1

Representative bullous pemphigoid patients without the coincidence of neurodegenerative disorder (BP − ND) without an overt malignancy. (a) A middle-aged man with BP presenting itchy blisters on an erythematous base on the thigh and having ELISA anti-BP180 IgG >200 RU/mL, ELISA anti-BP230 IgG >200 RU/mL (cutoff = 20 RU/mL). (b) An octogenarian man with erythrodermic BP having ELISA anti-BP180 IgG >200 RU/ml, ELISA anti-BP230 IgG 73.713 RU/ml (cut-off 20 RU/ml) in whom histopathological examination revealed subepidermal blister with a mixed inflammatory infiltrate containing eosinophils underneath (hematoxylin and eosin staining, original objective magnification ×40)

We examined here, whether neural system antigens are recognized by the antibodies from BP patients as, to the best of our knowledge, there is a lack of data concerning the conceptual role of anti-neuronal antibodies underlying the risk of development of BP in ND patients.

Thirty BP patients with the coincidence of ND (BP+ND) and 30 BP patients without the coincidence of ND (BP−ND) were investigated.

Sera were tested by immunoblotting using the Neuronal Antigens Profile Plus RST kit (Euroimmun, Luebeck, Germany) for antibodies to the panel of individual neuronal antigens [Figure 2], whereas antibodies to BP180/BP230 were detected with commercially available enzyme-linked immunosorbent assays (ELISAs) (Euroimmun, Luebeck, Germany). Statistical analyses were performed using statistical analysis Software Statistica PL 10.0 (StatSoft Inc.).

Figure 2

Representative results of immunoblotting in examined groups: (a) an 82-year-old man with BP and Parkinson's disease without malignancies. Direct immunofluorescence revealed linear IgG4 (+) and C3 (+++) along the dermal-epidermal junction; ELISA anti-BP180 IgG 66.896 RU/mL, ELISA anti-BP230 IgG 114.511 RU/mL (cutoff = 20 RU/mL); (b) an elderly woman with BP without neurodegenerative disorders and malignancies. Direct immunofluorescence revealed linear IgG1 (+) and C3 (+++) along the dermal-epidermal junction; ELISA anti-BP180 IgG >200 RU/mL, ELISA anti-BP230 IgG 11.947 RU/mL (cutoff 20 RU/mL)

Negative correlations were found in BP + ND patients between the presence of anti-BP180 IgG and anti-Yo IgG antibodies (r = −0.430, P = 0.0318) and in BP − ND patients between the presence of anti-BP180 IgG and anti-CRMP-5 IgG antibodies (r = −0.402, P = 0.0308).

The percentage of the occurrence of examined anti-neuronal antibodies in both groups (BP+ND, BP−ND) is presented in Table 1.

Table 1

The comparison of the percentage of positive results of anti-neuronal IgG in bullous pemphigoid patients with the coincidence of neurodegenerative disorder (BP+ND) and bullous pemphigoid patients without the coincidence of neurodegenerative disorder (BP−ND) with difference test between two proportions

	Positive results		P
	BP+ND (n=30)	BP−ND (n=30)
Titin	7%	10%	0.6770
SOX1	3%	0%	0.3391
Rec	3%	0%	0.3391
Hu	0%	0%	1.0000
Yo	0%	0%	1.0000
Ri	0%	0%	1.0000
Ma2/Ta	13%	3%	0.1534
CV2	0%	3%	0.3391
Amp	3%	0%	0.3391

BP: Bullous pemphigoid; ND: Neurodegenerative disorders, Amp: Amphiphysin; Rec: Recoverin

Fisher's exact test revealed a lack of association between reactivity against any antigens that are present in the immunoblot in examined groups (BP + ND and BP − ND; P = 1.000).

Our findings gently suggest that PNMA2 in patients with ND may be a herald of BP, however, further investigations with a larger population and longer follow-up are needed. The observations reported here may indicate the immunogenetic mechanisms involved in the association between ND and BP. Messingham et al.[3] suggested that the initial loss of tolerance to neuronal BP180 may contribute to the risk of subsequent development of cutaneous BP. It is also postulated that the HLA-DQB1*03:01 allele, with a well-established role in susceptibility to the pemphigoids, may serve as an additional link between ND and BP, catalyzing the process of epitope spreading from neuronal BP180 to hemidesmosomal BP180 or vice versa.[4] In addition, a possible genetic background of ND and BP may also be related to the chromosomal assignment.

There is no relationship between IgG antibodies to BP180/BP230 and IgG anti-neuronal antibodies in BP+ND. Nevertheless, it is speculated that PNMA2-collagen interactions in certain patients might be associated with the coexistence of BP with ND irrespective of malignancy suggesting the necessity of holistic treatment strategies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.