Autoimmune diseases in dermatology

Dr Rosie Chellet, Medical Registrar, Christchurch Hospital, Christchurch, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, New Zealand. Copy edited by Gus Mitchell. April 2019.


What is the immune system?

The immune system is made up of the cells, molecules and structures that defend the body from infectious disease and monitor for tissue damage [1].

Immune responses can be divided into innate immunity and adaptive immunity.

Innate immunity

Innate immunity describes generalised measures to ward off infection. These include:

  • Physical barriers, such as the skin and mucous membranes stop the majority of microorganisms entering [2].
  • White blood cells, such as macrophages, recognise microorganisms and release chemicals to stimulate and attract other immune cells.
  • Neutrophils, envelope and digest invading microorganisms by a process called phagocytosis (cellular ‘eating’).

Innate immune responses are often accompanied by inflammation [3].

Adaptive immunity

Adaptive immunity describes slower immune responses, including the production of immune cells that produce specific antibodies to target and remove a particular microorganism [1].

  • In cell-mediated immunity, T lymphocytes are produced that are conditioned to eliminate intracellular pathogens (viruses and bacteria) [4].
  • In humoral immunity, antibody-producing B lymphocytes deal with extracellular pathogens (encapsulated bacteria) [4].

Adaptive immunity results in the production of memory T lymphocytes and B lymphocytes that are able to specifically target a particular infection. These lymphocytes continue to circulate and quickly recognise and remove the virus or bacteria when it is next encountered [3].

What is autoimmunity?

Autoimmunity is an immune response against the self and usually involves T and B lymphocytes. The particular targeted protein or structure is called the self-antigen [3].

Autoimmunity may result in autoimmune disease with tissue damage or impaired physiological function. Autoimmune responses may also occur without causing disease [3].

Antibodies that react against self-antigens are called autoantibodies. In some autoimmune diseases, autoantibodies are the direct cause of tissue damage. In others, autoantibodies may be present without causing injury [5].

Examples of autoimmune diseases include:

Autoimmune skin diseases

Autoimmune blistering skin diseases include:

Autoimmune bullous diseases

Autoimmunity and deregulation of the immune system also contribute to many skin diseases, such as:

Autoimmune skin diseases

Who gets autoimmune diseases?

Autoimmune diseases affect around 5% of the population [3].

  • Most autoimmune diseases are more common in women [3].
  • People with a family history of autoimmune disease are at higher risk of developing one themselves [6].
  • Some studies show them to be more common among higher socioeconomic groups and at northern latitudes [3].
  • Autoimmune blistering skin diseases are rare and have fairly similar rates in both men and women [7].

What causes autoimmune diseases?

Autoimmune disease occurs when the responses that normally prevent autoimmunity fail [5]. There are several protective mechanisms.

  • Maturing T lymphocytes in the thymus, a lymphoid organ found between the lungs where the T cells develop and mature, are removed if they react strongly against self-antigens [3].
  • Circulating T-regulatory cells suppress immune responses [5].
  • B lymphocytes that react strongly against self-antigens can undergo receptor editing and change their B cell receptor [5].
  • T and B lymphocytes in the circulation need co-stimulation by other immune cells to become active [5].

The exact cause of a particular autoimmune disease is often not fully understood. Risk factors for many autoimmune diseases include genetic factors, infections, hormones, and drugs.

  • Genetic factors are most commonly polygenic (multiple genes combine to increase risk) [1].
  • Infections may trigger an autoimmune process by mimicking a self-antigen or by increasing co-stimulatory molecules [1].
  • Genes on the Y chromosome may protect men from autoimmune disease, and oestrogen may play a role in the increased susceptibility of women to autoimmune diseases [1].
  • Certain drugs (eg, penicillamine, captopril and vancomycin) can precipitate pemphigus vulgaris and pemphigus foliaceus [8].

Well-designed trials have concluded that there is no evidence that vaccines cause autoimmune disease [5].

Autoimmune blistering diseases

The autoimmune cause of this class of blistering diseases is confirmed by positive direct immunofluorescence microscopy revealing the deposition of antibodies in the skin.

Pemphigus

Pemphigus is a group of rare blistering disorders caused by circulating autoantibodies that bind to adhesion molecules in the skin, which disrupts the way keratinocytes stick together, causing intraepidermal blisters [9]. The main types of pemphigus are pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus [9].

  • Pemphigus vulgaris is characterised by blisters and erosions inside the mouth as well as on the skin. There are circulating autoantibodies against desmoglein-3, which is a protein important in keratinocyte cell-to-cell adhesion [10].
  • Pemphigus foliaceus causes superficial blisters typically on the trunk, scalp and face. There are autoantibodies against desmoglein-1 [3].
  • Paraneoplastic pemphigus causes blistering and ulceration in the mouth and sometimes the skin, arising in association with malignancy, most often a non-Hodgkin lymphoma. Multiple autoantibodies in paraneoplastic pemphigus include those targeting desmoplakin proteins [11].

Pemphigoid

The pemphigoid group of diseases includes bullous pemphigoid, mucous membrane pemphigoid, and pemphigoid gestationis. Pemphigoid blisters are subepidermal and are caused by autoantibodies that bind in the area of the dermal-epidermal junction [9].

  • Bullous pemphigoid predominantly affects older people who present with large tense fluid-filled blisters and erosions, often preceded by urticated or eczematous plaques [12]. There are antibodies against BP180, a hemidesmosome-associated protein involved in keratinocyte to basement membrane adhesion, and against BP230, a protein in basal keratinocytes [9].
  • Mucous membrane pemphigoid is characterised by recurrent blistering and ulceration of mucous membranes, particularly the mouth and eyes, and can also affect the skin [9]. The split occurs lower in the dermal-epidermal junction leading to scarring. Several autoantibodies have been associated with differing presentations of mucous membrane pemphigoid including BP180, BP230, laminin 332, alpha6beta4 integrin, and type VII collagen.
  • Pemphigoid gestationis affects women during pregnancy or shortly after delivery. It often starts as an intensely itchy urticaria-like rash around the belly button and then may spread to involve the entire skin surface, but not mucous membranes. It later typically progresses to tense blisters resembling those of bullous pemphigoid [13]. BP180 antibodies may be detected. The primary site of autoimmunity is thought to be the placenta.

Other rare blistering diseases

Dermatitis herpetiformis is an itchy blistering skin disease that typically affects elbows, knees and buttocks. It is associated with coeliac disease, and the symptoms heal with a gluten-free diet [15]. Blisters and deposition of IgA are subepidermal and a neutrophilic infiltrate is characteristic. The antibodies target epidermal transglutaminase [14].

Linear IgA bullous dermatosis is a very rare autoimmune blistering disorder that can be acquired or drug-induced (eg, by vancomycin). The blisters are sometimes arranged in rings, known as the ‘pearl necklace’ sign [9]. There is subepidermal deposition of IgA antibodies targeting a portion of the BP180 antigen, type VII collagen, or other basement membrane proteins.

Epidermolysis bullosa acquisita is also very rare. In the classical form, blisters and erosions form at areas of minor trauma [9]. The autoantibodies are directed against type VII collagen in anchoring fibrils in the basement membrane zone of the skin and mucosa.

How are autoimmune diseases in dermatology diagnosed?

A biopsy is usually needed for a definitive diagnosis of an autoimmune skin disease, although a characteristic appearance may be suggestive of a particular condition [9].

Blood tests may include:

  • Circulating skin autoantibodies (indirect immunofluorescence) [15]
  • Coeliac antibodies, such as IgA tissue transglutaminase antibodies (tTG antibodies)
  • Nonspecific tests for inflammatory markers (eg, CRP)
  • Autoimmune screen (eg, ANA).

Swabs of a ruptured blister may be taken to look for signs of a bacterial infection or herpes virus infection.

What is the differential diagnosis for autoimmune blistering skin diseases?

Blistering skin rashes associated with systemic illness may present with fever and ‘flu-like' symptoms [15]. These disorders can include:

Other generalised blistering disorders that present with autoimmune skin disease symptoms include:

Blistering of mucous membranes is also a common symptom in these conditions:

What is the treatment for autoimmune skin diseases?

The treatment of autoimmune skin diseases depends on the specific condition.

Pemphigus and pemphigoid are mainly treated with systemic corticosteroids and immunosuppressive treatments [16].

Dermatitis herpetiformis is treated with dapsone and a gluten-free diet [14].

 

Related information

 

References

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  2. Johnstone RB, Orange JS, Feldweg AM. An overview of the innate immune system. UpToDate. Updated 07 Nov 2017. Available at: www.uptodate.com/contents/an-overview-of-the-innate-immune-system (accessed 4 February 2018).
  3. Chapel H, Haeney M, Misbah S, Snowden N. Essentials of Clinical Immunology, 6th edn. Wiley-Blackwell, 2014.
  4. Maddoff LC, Kasper DL. Introduction to Infectious Diseases: Host-Pathogen Interactions. Harrison’s Principles of Internal Medicine, 18th edn. McGraw-Hill, 2012: 1000–12.
  5. Rose NR. Overview of Autoimmunity. UpToDate. Updated 10 July 2017. Available at: http://www.uptodate.com/contents/over-view-of-autoimmunity (accessed 7 February 2018).
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  7. Bickle KM, Roark TR, Hsu S. Autoimmune Bullous Dermatoses: A Review. Am Fam Physician 2002; 65: 1861–71. PubMed
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  9. Baum S, Sakka N, Artsi O, Trau H, Brazilai A. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev 2014; 13: 482–89. PubMed
  10. Habif T. Vesicular and Bullous Diseases. Clinical Dermatology. Mosby Elselvier, 2010: 635–70.
  11. Anhalt GJ. Paraneoplastic pemphigus. UpToDate. Updated 5 October 2017. Available at: https://www.uptodate.com/contents/paraneoplastic-pemphigus (accessed 1 March 2018).
  12. Yancey KB, Lawley TJ. Immunologically Mediated Skin Diseases. Harrison’s Principles of Internal Medicine, 18th edn. McGraw-Hill, 2012: 424–31.
  13. Ambros-Rudolph CM. Dermatoses of pregnancy – clues to diagnosis, fetal risk and therapy. Ann Dermatol 2011; 23: 265–75. PubMed Central
  14. Collin P, Salmi TT, Hervonen K, Kaukinen K, Reunala T. Dermatitis herpetiformis: a cutaneous manifestation of celiac disease. Ann Med 2017; 49: 23–31. PubMed
  15. Hull C, Zone J. Approach to patient with cutaneous blisters. UpToDate. Updated July 10, 2017. Available at: www.uptodate.com/contents/approach-to-the-patient-with-cutaneous-blisters (accessed 21 April 2018).
  16. Kayani M, Aslam AM. Bullous pemphigoid and pemphigus vulgaris. BMJ 2017; 357: j2169. Journal

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