Hypersensitivity reactions in the skin

Hypersensitivity reactions in the skin

Hypersensitivity is the term given to an exaggerated or inappropriate immune reaction. It is still helpful, if rather artificial, to separate these into four main types using the original classification of Coombs and Gell. All of these types underlie reactions in the skin.

Type I: immediate hypersensitivity reactions

These are characterized by vasodilatation and an out-pouring of fluid from blood vessels. Such reactions can be mimicked by drugs or toxins, which act directly, but immunological reactions are mediated by anti-bodies, and are manifestations of allergy. IgE and IgG4 antibodies, produced by plasma cells in organs other than the skin, attach themselves to mast cells in the dermis. These contain inflammatory mediators, either in granules or in their cytoplasm. The IgE anti-body is attached to the mast cell by its Fc end, so that the antigen combining site dangles from the mast cell like a hand on an arm (Fig. 2.14). When specific antigen combines with the hand parts of the immuno-globulin (the antigen-binding site or Fab end), the mast cell liberates its mediators into the surround-ing tissue. Of these mediators, histamine (from the granules) and leukotrienes (from the cell membrane) induce vasodilatation, and endothelial cells retract allowing transudation into the extravascular space. The vasodilatation causes a pink colour, and the tran-sudation causes swelling. Urticaria and angioedema  are examples of immediate hypersensitivity reactions occurring in the skin.

Antigen may be delivered to the skin from the out-side (e.g. in a bee sting). This will induce a swelling in everyone by a direct pharmacological action. However, some people, with IgE antibodies against antigens in the venom, swell even more at the site of the sting as the result of a specific immunological reaction. If they are extremely sensitive, they may develop wheezing, wheals and anaphylactic shock (see Fig. 22.5), because of a massive release of histamine into the circulation.

Antigens can also reach mast cells from inside the body. Those who are allergic to shellfish, for example, may develop urticaria within seconds, minutes or hours of eating one. Antigenic material, absorbed from the gut, passes to tissue mast cells via the circulation, and elicits an urticarial reaction after binding to specific IgE on mast cells in the skin.

Type II: humoral cytotoxic reactions

In the main, these involve IgG and IgM antibodies, which, like IgE, are produced by plasma cells and are present in the interstitial fluid of the skin. When they meet an antigen, they fix and activate complement through a series of enzymatic reactions that generate mediator and cytotoxic proteins. If bacteria enter the skin, IgG and IgM antibodies bind to antigens on them. Complement is activated through the classical pathway, and a number of mediators are generated. Amongst these are the chemotactic factor, C5a, which attracts polymorphs to the area of bacterial invasion, and the opsonin, C3b, which coats the bacteria so that they can be ingested and killed by polymorphs when these arrive (Fig. 2.15). 

Under certain circumstances, activation of complement can kill cells or organisms directly by the ‘membrane attack complex’ (C5b6789) in the terminal complement pathway. Complement can also be activated by bacteria directly through the altern-ative pathway; antibody is not required. The bacterial cell wall causes more C3b to be produced by the altern-ative pathway factors B, D and P (properdin). Aggreg-ated IgA can also activate the alternative pathway.

Activation of either pathway produces C3b, the pivotal component of the complement system. Through the amplification loop, a single reaction can flood the area with C3b, C5a and other amplification loop and terminal pathway components. Complement is the mediator of humoral reactions.

Humoral cytotoxic reactions are typical of defence against infectious agents such as bacteria. However, they are also involved in certain autoimmune diseases such as pemphigoid .

Occasionally, antibodies bind to the surface of a cell and activate it without causing its death or activating complement. Instead, the cell is stimul-ated to produce a hormone-like substance that may mediate disease. Pemphigus  is a blistering disease of skin in which this type of reaction may be important.

Type III: immune complex-mediated reactions

Antigen may combine with antibodies near vital tissues so that the ensuing inflammatory response damages them. 

When an antigen is injected intradermally, it combines with appropriate antibodies on the walls of blood vessels, complement is activated, and polymor-phonuclear leucocytes are brought to the area (an Arthus reaction). Degranulation of polymorphs liber-ates lysosomal enzymes that damage the vessel walls.

Antigen–antibody complexes can also be formed in the circulation, move to the small vessels in the skin and lodge there (Fig. 2.16). Complement will then be activated and inflammatory cells will injure the vessels as in the Arthus reaction. This causes oedema and the extravasation of red blood cells (e.g. the palpable purpura that characterizes vasculitis; ).

Type IV: cell-mediated immune reactions

As the name implies, these are mediated by lymphocytes rather than by antibodies. Cell-mediated immune reac-tions are important in granulomas, delayed hypersensi-tivity reactions, and allergic contact dermatitis. They probably also play a part in some photosensitive dis-orders, in protecting against cancer, and in mediating reactions to insect bites.

Allergic contact dermatitis

There are two phases: during the induction phase naïve lymphocytes become sensitized to a specific antigen; during the elicitation phase antigens entering the skin are processed by antigen-presenting cells such as macrophages and Langerhans cells (Fig. 2.17) and then interact with sensitized lymphocytes. The lympho-cytes are stimulated to enlarge, divide and to secrete cytokines that can injure tissues directly and kill cells or microbes.

Induction (sensitization) phase (Fig. 2.17)

When the epidermal barrier is breached, the immune system provides the second line of defence. Among the keratinocytes are Langerhans cells, highly specialized intraepidermal macrophages with tentacles that inter-twine among the keratinocytes, providing a net (Fig. 2.7) to ‘catch’ antigens falling down on them from the surface, such as chemicals or the antigens of microbes or tumours. During the initial induction phase, the antigen is trapped by a Langerhans cell which then migrates to the regional lymph node. To do this, it must retract its dendrites and ‘swim upstream’ from the prickle cell layer of the epidermis towards the base-ment membrane, against the ‘flow’ of keratinocytes generated by the epidermal basal cells. 

Once in the dermis, the Langerhans cell enters the lymphatic sys-tem, and by the time it reaches the regional lymph node it will have processed the antigen, which is re-expressed on its surface in conjunction with MHC Class II molecules. In the node, the Langerhans cell mingles with crowds of lymphocytes, where it is most likely to find a T cell with just the right T-cell receptor to bind its now processed antigen. Helper (CD4+) T lymphocytes recognize antigen only in the presence of cells bearing MHC Class II antigens, such as the Langerhans cell. The interactions between surface molecules on a CD4+ T cell and a Langerhans cell are shown in Fig. 2.12. When a T cell interacts with an antigen-presenting cell carrying an antigen to which it can react, the T lymphocyte divides. This division depends upon the persistence of antigen (and the antigen-presenting cells that contain it) and the T-cell growth factor interleukin-2 (IL-2). Eventually, a whole cadre of memory T cells is available to return to the skin to attack the antigen that stimulated their proliferation.

CD4+, CD45+ memory T lymphocytes circulate between nodes and tissues via lymphatic vessels, the thoracic duct, blood and interstitial fluid. They return to the skin aided by ‘homing molecules’ (cutaneous lymphocyte antigen, CLA) that guide their trip so that they preferentially enter the dermis. In the absence of antigen, they merely pass through it, and again enter the lymphatic vessels to return and recirculate. These cells are sentinel cells (Fig. 2.18), alert for their own special antigens. They accumulate in the skin if the host again encounters the antigen that initially

stimulated their production. This preferential circula-tion of lymphocytes into the skin is a special part of the ‘skin immune system’ and reflects a selective advantage for the body to circulate lymphocytes that react to skin and skin surface-derived antigens.

Elicitation (challenge) phase (Fig. 2.18)

When a T lymphocyte again encounters the antigen to which it is sensitized, it is ready to react. If the antigen is extracellular, as on an invading bacterium, toxin or chemical allergen, the CD4+ T-helper cells do the work. The sequence of antigen processing by the Langerhans cell in the elicitation reaction is similar to the sequence of antigen processing during the induction phase, described above, that leads to the induction of immun-ity. The antigens get trapped by epidermal Langerhans cells or dermal dendritic cells, which process the anti-gen intracellularly before re-expressing the modified antigenic determinant on their surfaces. In the elicita-tion reaction, the Langerhans cells find appropriate T lymphocytes in the dermis, so most antigen presenta-tion occurs there. The antigen is presented to CD4+ T cells which are activated and produce cytokines that cause lymphocytes, polymorphonuclear leucocytes and monocytes in blood vessels to slow as they pass through dermal blood vessels, to stop and emigrate into the dermis causing inflammation (Fig. 2.18). Helper or cytotoxic lymphocytes help to stem the infection or eliminate antigen and polymorphonuclear leucocytes engulf antigens and destroy them. The traffic of inflam-matory cells in the epidermis and dermis is determined not only by cytokines produced by lymphocytes, but also by cytokines produced by injured keratinocytes (Fig. 2.11). For example, keratinocyte-derived cytokines can activate Langerhans cells and T cells, and IL-8, produced by keratinocytes, is a potent chemotactic factor for lymphocytes and polymorphs, and brings these up into the epidermis.

Response to intracellular antigens

Antigens coming from inside a cell, such as intra-cellular fungi or viruses and tumour antigens, are presented to cytotoxic T cells (CD8+) by the MHC Class I molecule. Presentation in this manner makes the infected cell liable to destruction by cytotoxic T lymphocytes or K cells. NK cells can also kill such cells, even though they have not been sensitized with antibody.

Granulomas

Granulomas form when cell-mediated immunity fails to eliminate antigen. Foreign body granulomas occur because material remains undigested. Immuno-logical granulomas require the persistence of antigen, but the response is augmented by a cell-mediated immune reaction. Lymphokines, released by lympho-cytes sensitized to the antigen, cause macrophages to differentiate into epithelioid cells and giant cells. These secrete other cytokines, which influence inflam-matory events. Immunological granulomas of the skin are characterized by Langhans giant cells (not to be confused with Langerhans cells;), epithelioid cells, and a surrounding mantle of lymphocytes.

Granulomatous reactions also occur when organ-isms cannot be destroyed (e.g. in tuberculosis, leprosy, leishmaniasis), or when a chemical cannot be eliminated (e.g. zirconium or beryllium). Similar reactions are seen in some persisting inflammations of undetermined cause (e.g. rosacea, granuloma annulare, sarcoidosis, and certain forms of panniculitis).