Immunologic Mechanism of Pathogenic Autoantibody Production in Pemphigus

CHAPTER
Immunologic Mechanism of Pathogenic

29
Fig. 29.5 Pemphigus

vulgaris – oral
Autoantibody Production in Pemphigus involvement. Essentially
Pemphigus
In contrast to the significant progress since the late 1980s in under- all patients develop
standing the pathophysiologic mechanisms of blister formation in pem- painful oral mucosal
phigus, it is still unclear why patients with pemphigus begin to produce erosions. The most
common sites are the
the pathogenic autoantibodies. buccal (A) and palatine
Pemphigus autoantibodies are composed of IgG isotypes, which may mucosae, but lesions can
be produced after isotype switching, and they have a high affinity also develop on the
towards the antigen, which may be a result of affinity maturation of gingivae (B) and tongue
the antibodies. In addition, pemphigus sera recognize several distinct (C). A, Courtesy, Lorenzo Cerroni,
epitopes on desmogleins31, and the presence of autoantibodies is associ- MD; B,C, Courtesy, Jeffrey P Callen,
ated with specific HLA class II alleles, including DRB1*0402, MD.
A
DRB1*1401 and DQB1*0302 in Caucasians39 and DRB1*14 and
DQB1*0503 in Japanese40. All of these features suggest that autoanti-
body production in pemphigus is T cell-dependent. More recently, T
cells reactive against Dsg3 were shown to be present in peripheral blood
from patients with pemphigus vulgaris as well as healthy individuals41–43.
Certain peptides from Dsg3, predicted to fit into the DRB1*0402
pocket, were able to stimulate T cells from the pemphigus patients.
Another advance that will allow the study of T cells and B cells is
the development of an active disease mouse model for pemphigus vul-
garis44. This model is valuable not only for dissecting the cellular and
molecular mechanisms involved in antibody production but also for
developing novel therapeutic strategies.
B
CLINICAL FEATURES
Pemphigus Vulgaris
Essentially all patients with pemphigus vulgaris develop painful ero-
sions of the oral mucosa. More than half of the patients also develop
flaccid blisters and widespread cutaneous erosions. Pemphigus vulgaris
is therefore divided into two subgroups: (1) the mucosal-dominant type
with mucosal erosions but minimal skin involvement; and (2) the
mucocutaneous type with extensive skin blisters and erosions in addi-
tion to mucosal involvement (see Fig. 29.4).
Mucous membrane lesions usually present as painful erosions
(Fig. 29.5). Intact blisters are rare, probably because they are fragile
and break easily. Although scattered or extensive erosions may be C
seen anywhere in the oral cavity, the most common sites are the
buccal and palatine mucosa. The erosions are of different sizes
with an irregular and ill-defined border, which, when extensive or
painful, may result in decreased oral intake of food or liquids. The
diagnosis of pemphigus vulgaris tends to be delayed in patients pre-
UNUSUAL CLINICAL PRESENTATIONS OF PEMPHIGUS VULGARIS
senting with only oral involvement, as compared to patients with
skin lesions. Isolated crusted plaque on face or scalp
The lesions may extend out onto the vermilion lip and lead to thick, Paronychia and/or onychomadesis
fissured hemorrhagic crusts. Involvement of the throat produces hoarse- Foot ulcers
ness and difficulty in swallowing. The esophagus also may be involved Dyshidrotic eczema or pompholyx
and sloughing of its entire lining in the form of a cast has been reported. Macroglossia
The conjunctivae, nasal mucosa, vagina, labia, penis and anus can
Table 29.3 Unusual clinical presentations of pemphigus vulgaris.
develop lesions as well. Cytology of vaginal cells may be misread as a
malignancy when vaginal lesions are present.

The primary skin lesions of pemphigus vulgaris are flaccid, thin-
walled, easily ruptured blisters (Fig. 29.6). They can appear anywhere
on the skin surface and arise on either normal-appearing skin or erythe-
treatment, pemphigus vulgaris can be fatal because a large portion of
matous bases. The fluid within the bullae is initially clear but may
the skin loses its epidermal barrier function, leading to the loss of body
become hemorrhagic, turbid, or even seropurulent. The blisters are
fluids or to secondary bacterial infections.
fragile and soon rupture to form painful erosions that ooze and bleed
easily. These erosions often attain a large size and can become general-
ized. The erosions soon become partially covered with crusts that have Pemphigus Vegetans
little or no tendency to heal. Those lesions that do heal often leave Pemphigus vegetans is a rare vegetative variant of pemphigus vulgaris,
hyperpigmented patches with no scarring. Associated pruritus is and it is thought to represent a reactive pattern of the skin to the
uncommon. Table 29.3 outlines more unusual clinical presentations of autoimmune insult of pemphigus vulgaris.
pemphigus vulgaris. Pemphigus vegetans is characterized by flaccid blisters that become
Because of an absence of cohesion within the epidermis, its upper erosions and then form fungoid vegetations or papillomatous prolifera-
layers easily move laterally with slight pressure or rubbing in patients tions, especially in intertriginous areas and on the scalp or face (Fig.
with active disease (Nikolsky sign). The lack of cohesion of the skin 29.7). Pustules rather than vesicles characterize early lesions, but these
may also be demonstrated with the “bulla-spread phenomenon” – soon progress to vegetative plaques. The tongue may show cerebriform-
gentle pressure on an intact bulla forces the fluid to spread under the like changes. Two subtypes are recognized: the severe Neumann type
skin away from the site of pressure (Asboe–Hansen sign, also referred and the mild Hallopeau type. Occasionally, a vegetative response may 499
to as the “indirect Nikolsky” or “Nikolsky II” sign). Without appropriate also be seen in lesions of pemphigus vulgaris that tend to be resistant

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CHAPTER

Immunologic Mechanism of Pathogenic

malignancy when vaginal lesions are present.

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