Diagnosis and Pathophysiology of IgA Mediated Bullous Dermatosis

Diagnosis and Pathophysiology of IgA Mediated Bullous Dermatosis
Medical Terminology

1) Bullous (blistering)
2) Keratinocyte (An epidermal cell that produces keratin)
3) BMZ (Base Membrane Zone)
4) Epidermis.(the upper layer of the skin )
5) acantholysis (loss of cohesion between the epidermal cells, resulting in intraepidermal clefts, vesicles and bullae found in autoimmune skin diseases. )
6) anchoring filaments (thread-like fibres )
7) Hemidesmosomes (Hem-ee-DES-mo-so-m's. complex structures composed of many proteins)
8) Dermis (lower layer of the skin)
9) pruritis (itching)

Concerning Ocular Involvement in IgA Mediated Bullous Skin Disease
Please note that it is widely accepted that ANY bullous disease has the potential to affect the mucous membranes, in particular IgA mediated bullous diseases, as the IgA immunoglobulin antibody is the antibody most dominant found in the secretions of tears and saliva. About 80% of people with Linear IgA disease have mucosal involvement. It is untrue that Liga (LaD) or IgA mediated EBA does not affect the "inside" of the body. It CAN!! for the reasons stated above. It is also totally untrue that LigA does not affect the eyes. It CAN!!
Note too, it is published in many articles, that the resulting manifestations in mucosal involvement in Linear IgA disease and IgA mediated Epidermolysis Bullosa Aquisita, are indistinguishable from Cicatricial Pemphigoid when manifesting in mucous membranes. (therefore treatment and caution is the same!)

Following Extract from..... please note in bold

Autoimmune diseases are extremely diverse in origin, pathogenesis and clinical ocular manifestations. As a group, these diseases are the ones that clinicians think of as the most destructive to the ocular surface. No matter whether the pathologic mechanism is neutrophilmediated, immune-complex-mediated, or T-cell-mediated, the end result is scarring or destruction of ocular tissues and interference with the physiologic processes necessary to maintaining ocular surface homeostasis.
Understanding the management of patients with this group of diseases requires a comprehensive understanding of how all of the components of the ocular surface work together. The clinician responsible for caring for patients who suffer from these diseases must simultaneously manage eyelid and meibomian gland disease, conjunctival and episcleral inflammatory disease, tear film disorders and keratitis, which may be exposure-related, infectious, inflammatory, toxic, or combinations of all these categories.

While the details of treating autoimmune diseases vary with each specific disease entity, it is critical that the treating clinician remain constantly aware of the interactions between all of the components of the ocular surface and direct appropriate treatment toward each abnormality simultaneously.
Just as it is impossible to provide comfort to the dry eye patient with blepharitis by using ocular lubricants alone, the severe pathologies involved in autoimmune diseases require a multi-armed therapeutic approach.

Bearing in mind that there is no clinical difference between Cicatricial pemphigoid and either of these two IgA mediated Bullous conditions, when affecting these tissues.....

Cicatricial pemphigoid is an autoimmune, cicatrizing disease of mucosal epithelium and, less often, skin. Cicatricial pemphigoid (CP) was first defined as a disease entity separate from pemphigus by Thost in 1911. It has been termed “chronic pemphigus,” “essential shrinkage of the conjunctiva,” “ocular pemphigus” and has been widely described as “benign mucous membrane pemphigoid” in dermatologic literature.
Since this disease is often anything but benign with regard to its ophthalmic consequences, the term cicatricial pemphigoid is suggested as the preferred terminology and will be used herein.
To the ophthalmologist, the usual presentation is chronic conjunctivitis with an insidious onset. The course of the disease is usually slow but may be punctuated by periods of explosive inflammatory activity. Ten to thirty years or more may be required for the disease to run its full course, with bilateral blindness as the result. Unilateral presentation is not rare, but eventually most patients develop bilateral ocular involvement; slowly progressive subconjunctival cicatrization is the hallmark of this disease.
Sixty-five to ninety percent of CP patients have ocular involvement, while approximately 25% have lesions on non-mucosal skin. Oral disease occurs in 70–90% of CP patients, and the mouth may be the sole site of involvement. Desquamative gingivitis is the most common oral manifestation, although nonhealing ulcers of buccal mucosa are not rare. Commonly, bullae develop after local trauma during chewing, and last several days. Once the bullae rupture, nonhealing erosions may last for weeks. Involvement of nasal, pharyngeal, laryngeal, esophageal, urethral, vaginal or anal mucosal surfaces may manifest as chronic ulcerations or strictures.
(Bear in mind that 80% of patients with IgA mediated Bullous disease have mucosal involvement)

The diagnosis can be difficult, as linear IgA disease can mimic several other disorders. Confirmation of the diagnosis requires a skin biopsy in which a smooth line of IgA under the epidermis can be shown up by a special test (direct immunofluorescence) and by (indirect immunofluorescence) on blood serum which shows circulating antibodies.

Direct immunofluorescence
A study of both perilesional skin and healthy skin typically shows linear deposition of IgA at the BMZ. Linear deposition of C3 may also be seen. Direct immunofluorescence study of salt-split skin reveals IgA deposition on either the dermal side (blister floor) or the epidermal side (blister roof). Some patients demonstrate both linear IgA deposition and immunoglobulin G (IgG) deposition at the BMZ. Immunoglobulin M (IgM) deposition has rarely been reported.

Indirect immunofluorescence
Studies are taken from samples of Serum from blood. Patients with LAD have detectable circulating antibody that binds to the BMZ. Sensitivity is greater for immunofluorescence studies performed on salt-split healthy human skin. Circulating antibody titers are typically low (1:10 to 1:20). When present, linear deposition of antibody is observed at the BMZ or at the blister roof or floor in salt-split skin. Children with LAD may demonstrate circulating anti-BMZ antibodies more frequently than adults.

Definition: of C3 Complement:- is a blood test that measures the activity of certain proteins in the liquid portion of blood. The complement system is a group of proteins that move freely through the bloodstream. The proteins work with the immune system and play a role in the development of inflammation. There are nine major complement proteins. They are labeled C1 through C9.
(see Immunity- Complement System -under Cells of the Immune System : )
The result of this Direct immunofluorescence test in link below

NB:-Recent complicated methods of testing, to determine these target antigens, are set up in laboratories in some countries, in particular Japan, but due to the complexities of the set up, these tests are not readily available worldwide. However Proff.Neil Cox of Carlisle Cumbria has carried out part of these tests on the blood of myself, to establish an accurate diagnosis.

Histologic Findings in biopsy
Early urticarial papules or plaques reveal neutrophils aligned along the BMZ accompanied by vacuolar change. Neutrophilic micro-abscesses may be seen in dermal papillae . Fully developed lesions reveal subepidermal blistering with a predominantly polymorphonuclear infiltrate, although mononuclear cells and eosinophils may be present.

Medical Terminology
See Definition of Vacuolar in link below

Neutrophils (see Neutrophils under Cells of the Immune System- Phagocytes)
Polymorphonuclear-(Having a nuclei of varied forms; denoting a variety of leukocyte-see neutrophils)
Mononuclear- (Having only one nucleus; used especially in reference to blood cells.)
Eosinophils- (see Eosinophils under Cells of the Immune System)

LAD is an autoimmune disease histopathologically characterized by the linear deposition of IgA at the basement membrane zone (BMZ). Antibody deposition leads to complement activation (see Complement System) and neutrophil chemotaxis, (see Chemotaxis ) which eventuates in loss of adhesion at the dermal-epidermal junction and in blister formation. Disease in children is immunologically identical to that of adults. The mechanism of loss of self-tolerance to target antigens is as yet uncertain.
Within the dermal-epidermal junction, different antigenic target sites, including the lamina lucida, the sublamina densa, or both locations simultaneously, have been identified.
The best-characterized antigen is a 97-kd protein extracted from human epidermis that binds IgA antibodies from sera of patients with LAD. Sera that binds the 97-kd antigen localizes to the lamina lucida of salt-split skin.
Originally thought to be a unique protein of the lamina lucida, recent work reveals that the 97-kd protein may represent a portion of the extracellular domain of the 180-kd bullous pemphigoid antigen (BPAg2).
The same patient sera have been shown to bind a 120-kd antigen in the BMZ. The 97- and 120-kd antigens may represent cleaved fragments of BPAg2, which exist as such in vivo or are produced by proteolytic digestion (The ability to break down protein molecules) in vitro. These smaller molecules could also be alternative splicing products of the same BPAg2 gene. Because antibodies that bind the 97- and 120-kd antigens do not recognize the 180-kd BPAg2, the former may express unique epitopes (see Epitopes) distinct from those of the parent protein.
A recent case series reported patients with sera not reactive against the 97-kd antigen but rather against both bullous pemphigoid antigens.
Of 11 patients, a 230-kd antigen (BPAg1) was recognized in 6 patients and BPAg2 was recognized in 5 patients.
The authors suggest that an IgA-specific immune response may occur against bullous pemphigoid antigens in LAD.
These results are provocative given that the 97-kd LAD antigen may represent a portion of the extracellular domain of BPAg2.
A 285-kd target antigen has been identified in the lamina lucida and the sublamina densa; this antigen is recognized by circulating antibodies in some patients with LAD, but it has not been further characterized.
A 250-kd dermal antigen corresponding to collagen VII of anchoring fibrils has also been reported as a target antigen in some patients.
LAD illustrates the importance of identifying the target antigen.
In cases where type VII collagen is the molecule against which the IgA antibody response is directed, patients are less likely to be responsive to treatment. Thus, viewing this condition as a subset of epidermolysis bullosa acquisita is better.
Similarly, patients with antibodies directed against the bullous pemphigoid antigens may be classified as having bullous pemphigoid but with an IgA response rather than an IgG response. Until more patients are reported whose antibody response is detailed to the molecular level and until this definition becomes clinically available, these heterogeneous patients will continue to be grouped into a single category, LAD. (see NB: above, under Diagnosis)

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