Bullous pemphigoid – causes, symptoms, diagnosis, treatment, pathology

Bullous pemphigoid is an autoimmune skin disease
that causes the skin to form bullae or blisters. Now, the skin is divided into three layers–the
epidermis, dermis, and hypodermis. The epidermis forms the thin outermost layer
of skin. Underneath, is the thicker dermis layer, and
finally, there’s the hypodermis that anchors the skin to the underlying muscle. The epidermis itself is made of multiple layers
of developing keratinocytes – which are flat pancake-shaped cells that are named for the
keratin protein that they’re filled with. Keratinocytes start their life at the lowest
layer of the epidermis called the stratum basale, or basal layer which is made of a
single layer of stem cells, called basal cells that continually divide and produce new keratinocytes. The stratum basale also contains another group
of cells called melanocytes, which secrete melanin. Melanin is a pigment protein, or coloring
substance. Below the epidermis is the basement membrane
which is a thin layer of delicate tissue containing collagen, laminins, and other proteins. Basal cells are attached to the basement membrane
by hemidesmosomes, a protein complex that stems from the bottom of the basal cells. Just like an anchor digs into the seafloor
and holds a boat in place, hemidesmosomes dig into the basement membrane and hold basal
cells in place. The exact cause of bullous pemphigoid is unclear,
but it’s thought that in a person with a genetic precondition, it can be triggered
by medications like furosemide, captopril, penicillamine, non steroid anti-inflammatory
drugs (or NSAIDs), and antibiotics. Bullous pemphigoid is a type II hypersensitivity
reaction, which is when the immune system produces antibodies that bind to the body’s
own cells. Immune cells called B cells produce IgG antibodies,
which are Y shaped molecules with 2 regions, an antigen binding fragment region – or Fab
region, and fragment crystallizable region or Fc region. The Fab region of the antibody binds to pathogens
which helps other immune cells destroy those pathogens. The antibodies can also activate a part of
the immune system called the complement system, which destroys the pathogen, or induces inflammation. In bullous pemphigoid, the Fab region of IgG
antibodies bind to proteins that make up the hemidesmosome: one of the proteins is called
bullous pemphigoid antigen 1 or BPAG1, which is also called dystonin, and another protein
is called bullous pemphigoid antigen 2 or BPAG2, which is also called BP 180 or type
17 collagen – lots of names for the same thing. The Fc region activates the complement system. The process gets started when C1, the first
of the complement proteins, binds the Fc region of the antibody. C1 then engages other members of the complement
family – C2 through C9, some of which are activated by being cleaved or chopped by an
enzyme. The cleaved fragments C3a, C4a, and C5a act
as chemotactic factors, meaning they attract certain cells, in this case the mast cells. The mast cells degranulate and release molecules
like tumor necrosis factor alpha, leukotrienes, and cytokines. These molecules attract inflammatory cells
like neutrophils, eosinophils, macrophages, and T cells. These inflammatory cells then secrete proteolytic
enzymes, which destroy the proteins of hemidesmosomes – BPAG1 and BPAG2. Now, If an anchor breaks it can no longer
hold the boat in place and it floats away. So, when the hemidesmosomes are destroyed
the basal cells separate from the basement membrane, and a split forms between the dermis
and epidermis, resulting in what’s called a subepidermal bullae. These subepidermal bullae are distinct from
the epidermal bullae which form in the disease pemphigus vulgaris. In fact, in pemphigus vulgaris the bullae
form as a results from breaking connections between cells within the epidermis. Now in bullous pemphigoid, the inflammation
also affects the melanocytes, which produce more melanin that gets stuck within the cells
of the dermis. Bullous pemphigoid is most commonly located
on the lower abdomen, flexor side of the forearms, and anterior or inner thighs, but can also
involve other areas as well. Unlike pemphigus vulgaris, it doesn’t typically
involve the oral mucosa. Early on, there’s a red and itchy rash,
and over time it develops into large bullae or blisters. The blisters typically evolve over a few days,
and leave behind crusted lesions that heal without scarring. A classic way to help distinguish bullous
pemphigoid from other skin diseases like pemphigus vulgaris is the Nikolsky’s sign – which
is when lateral pressure is applied to the lesion, and it causes a split to form between
the upper and lower layers of the epidermis. In bullous pemphigoid the skin doesn’t split. Pemphigus vulgaris will have the Nikolsky’s
sign, but bullous pemphigoid will not. In addition, a skin biopsy can be done to
look for evidence of antibodies and complement infiltration into the skin. Finally, the blood can be checked for auto-antibodies
against BPAG1 and BPAG2. Bullous pemphigoid is most commonly treated
by stopping any medications that could be triggering it and by using corticosteroids. All right, as a quick recap, bullous pemphigoid
is an autoimmune skin disease mediated by type II hypersensitivity. Autoantibodies form against BPAG1 and BPAG2,
and they allow blisters to form between the dermis and epidermis layers. Large tense blisters on the lower abdomen,
arms, and legs are the most common symptom. There is no Nikolsky’s sign, but there are
circulating IgG antibodies, and it’s usually treated with corticosteroids.


  1. Wow. Was literally looking after a patient who had bullous pemphigoid because of allergy to linagliptin. Took a month for her blisters to heal and a million parrafin oil tubes and hydrocort

  2. Onset 11/14… significant recovery 6/2017.  2018 only minor, occasional blistering and typically appearing below knees… and especially on old site locations.   Clobetasol , Benadryl 100mg every 4 hrs, doxycycline …. Prayers prayers and prayers….  and never blaming God.   Oddly, once returned to 'apparent' health… RLS began and the prime cause is Benadryl !! Benadryl was a significant reliever during this experience.. then it became the aggravator of RLS.   And…. be very aware that any use of pain medications… namely opioids… can be very counter productive since it allows exacerbation of all symptoms

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