Page 891 - Clinical Immunology_ Principles and Practice ( PDFDrive )

862 Part SEVEN Organ-Specific Inflammatory Disease

components of hemidesmosomes. These are the major attachment normal HLA-DQB1*03:01 showed similar T-cell reactivity but
sites of epidermal basal cells and where cytoskeletal proteins produced only T-helper-1 (Th1-type) cytokines, whereas T cells
link through the plasma membrane to the dermis. Two pre- from patients with BP produced both Th1-type and Th2-type
dominant antigens have been identified: 230-kDa and 180-kDa cytokines. These results suggest that the ability to mount Th2-
proteins. These have been cloned and sequenced, confirming pattern responses to BP antigen(s) may be critically important.
that they are distinct proteins, associated as a complex within
the hemidesmosome. The 230-kDa BP antigen (BPAG1) is an Therapy
intracellular protein with sequence homology to desmoplakin The mainstay of therapy for BP is treatment with systemic
I, a member of an adhesion junction plaque protein family. The glucocorticoids: most patients respond rapidly to oral prednisone
180-kDa BP antigen (BPAG2) contains both intracellular and (0.5–2.0 mg/kg/day), but starting prednisone at doses >0.75 mg/
extracellular domains joined by a transmembrane region. The kg/day confers no advantage. Mild or localized disease can
extracellular portion of BPAG2 has alternating collagen and sometimes be managed with potent topical corticosteroids
noncollagen domains and has been termed type XVII collagen. (confirmed in controlled trials). 31
Epitope mapping studies of BPAG2 have identified an immuno- When new blister formation has stopped and healing has
dominant epitope on an extracellular noncollagen linker domain begun, systemic steroids can be tapered slowly. The speed of
that is also targeted by IgG antibodies in PG. tapering is dictated by the severity of the patient’s initial disease
Although patients with BP have antibodies against BPAG1 and any flare-ups that occur during tapering. Most patients can
and BPAG2, the pathogenic role of these autoantibodies remains stop systemic steroids completely within 6–18 months, but
uncertain. Targeted disruption of the gene encoding BPAG1 did recurrence of disease activity is not uncommon. Flare-ups should
not result in blister formation or epidermal–dermal adhesion be managed with the lowest dose of systemic steroids possible;
abnormalities. This suggests that anti-BPAG1 antibodies may occasionally topical corticosteroids are enough. Usually, BP is
not directly inhibit the function of BPAG1 but may maintain or self-limiting, lasts between 1.5 and 5 years, and responds promptly
enhance the inflammatory response in BP. Interestingly, targeted to systemic glucocorticoids. 31
knockout of BPAG1 in mice causes progressive deterioration in A minority of patients requires prolonged high-dose systemic
motor function and sensory neurodegeneration. Additionally, glucocorticoids. In these individuals, adding azathioprine,
certain portions of BP230 (BPAG1n1 and BPAG1n3) seem to cyclophosphamide, or methotrexate will often allow tapering or
play important roles in organizing cytoskeletal networks in discontinuation of systemic steroids, but data on which is best
26
31
vivo. These findings complement prior studies implicating for steroid sparing are limited. Other unproven adjunctive
BP230 (BPAG1) in the function of the central nervous system of therapies that may help in some patients include dapsone,
humans and may explain the overlap between BP and neurological cyclosporine, and rituximab. Our preferred options for additional
diseases. 27 therapy are azathioprine (1–2 mg/kg/day) or mycophenolate
Patients with BP (and PG) develop antibodies against a mofetil (1000–2000 mg/day). 32
28
noncollagenous, extracellular portion of BPAG2. Serum levels A recent review of IVIG for BP concluded that 70% of patients
of BPAG2 autoantibodies correlate with disease activity in patients experienced some improvement but there was no clinical benefit
with BP. Interestingly, patients with an inherited form of skin in the remainder. IVIG 2 g/kg over 5 days at monthly intervals
blistering (generalized atrophic benign epidermolysis bullosa) for 3 months has been commonly used; typically more than one
have a mutation in BPAG2 resulting in a dysfunctional or missing cycle is needed to prevent recurrence. In some patients, IVIG
protein. 29 appears to be steroid sparing. IVIG was ineffective if patients
In an animal model of BP, rabbits were immunized to produce received low-dose IVIG or only a single infusion.
+
antibodies directed against mouse BPAG2. Passive transfer of Rituximab eliminates CD20 B cells through complement-
this rabbit IgG to newborn mice resulted in blisters, an inflam- dependent and antibody-dependent cell-mediated cytotoxicity,
matory infiltrate, and deposition of immunoreactants. In this as well as by inducing structural changes and apoptosis. The
model, complement activation, mast cell degranulation, and targeted B cells remain absent from the circulation for 6–12
neutrophil infiltration are important in blister formation. months. Several groups have reported clinical success with the
Complement activation and other extracellular mediators are use of rituximab for pemphigus, but it has only had limited
also implicated in the pathogenesis of BP skin lesions. Comple- success in the treatment of BP. 33
ment and the terminal components of the complement cascade An open-label trial of anti-IgE (omalizumab) demonstrated
34
are present in the skin of patients with BP. Early lesions in these benefit in 5 of 6 patients with BP, albeit with varying degrees
patients contain eosinophil granule proteins and eosinophil- of success.
derived gelatinase, suggesting an early role for eosinophils in the
lesion development. Taken together, these findings suggest that
IgG autoantibody binds, most likely, to BPAG2 and activates
complement and local cytokine production. This attracts KEY CONCEPtS
eosinophils and neutrophils that release enzymes leading to blister
formation. IgE antibodies against BPAG2 have also been found Bullous Pemphigoid
in sera from patients with BP and are implicated in the early Most common autoimmune blistering disease that presents in older
lesions of BP, the development of eosinophilic infiltration, and adults
degradation of the basement membrane zone. 30 Severely pruritic with clinical presentations, including urticarial lesions,
The factors that induce development of autoantibodies in small vesicles, and/or large tense vesicles
patients with BP are unknown. T cells from these patients Linear immunoglobulin G (IgG) and C3 present at the epidermal basement
membrane, binding to the epidermal side of “1 M NaCl split” skin
respond in vitro to the extracellular region of BPAG2; this Disease activity correlates best with IgG anti-BP 180 antibodies
reactivity is restricted by HLA-DQB1*03:01. Subjects with