Immune-Mediated Skin Disorders of Dogs

The immune system involves an extremely complicated process that serves as the body’s surveillance and defense systems. This process is continuously in flux and is still not completely understood. The immune system comprises 2 main components: innate (already present) and adaptive (created in response to a foreign substance in the body).¹ Although each system works differently (the innate immune system is based on blockades, and the adaptive immune system is based on cellular defense), each system provides protection from foreign proteins (i.e., antigens) such as viruses, bacteria, parasites, fungi, or anything that could be considered harmful to the body.

The basic premise underlying the concept of protective immunity is the ability to differentiate self from nonself. When this ability is compromised, immune-mediated skin disorders can occur. Before we delve into specific immune-mediated skin disorders, we will start with a quick immunology refresher.²

The Immune System

Innate Immune System

All living organisms have an innate immune system. This immune system is not specific; it is made up of a series of very general blockades put in place to keep stuff out. It doesn’t really care who comes knocking—they just are not getting in. For example, trees have bark, dogs have skin, and even bacteria have cell walls to protect them. The innate immune system serves as both first and second lines of defense.

First Line of Defense

This defense system is a pretty simple barrier system. It serves to keep foreign substances out of the body and includes the skin, chemical properties (e.g., the acidity of skin or stomach fluids), and sticky mucous membranes.

Second Line of Defense

This defense system comes into play after something has gotten past the first line of defense and entered the body. It includes the inflammatory response (which brings blood to the area so that white blood cells can get to work) and phagocytosis (the process by which cells remove pathogens and cell debris). Phagocytosis occurs when cells with receptors on their surfaces bind with antigens: in effect, trapping them. When these receptors become bound to antigens/pathogens, phagocytes are activated to wrap around the offenders to engulf and then digest them. The phagocyte will take some of the digested antigen/pathogen and bind it to a protein of its own, forming what is called a major histocompatibility complex (MHC) type II. MHCs type II are primarily present on antigen-presenting cells (i.e., macrophages and Langerhans cells that have engulfed foreign particles), whereas MHCs type I are present in nearly all nucleated cells in the body.

MHCs are kind of like name tags. Their presence on the surface of phagocytes enables other cells to determine whether they know what that phagocyte has killed. If it is something that they have seen before (i.e., if a memory cell for that antigen exists), they jump into action.

Several types of cells are capable of phagocytosis; after they have phagocytized pathogens or debris, they are called antigen-presenting cells (FIGURE 1). Neutrophils are usually the first on the scene as part of the inflammatory response, macrophages are slower to respond but can engulf more than neutrophils, and dendritic cells (in the skin, these are Langerhans cells) (FIGURE 2) are best at stimulating the adaptive immune system.

FIGURE 1. Antigen-presenting cell.

FIGURE 2. Dendritic cell with bacteria.

Complement System

Within the innate immune system is the complement system, which is composed of over 30 proteins and protein fragments. The adaptive immune system activates the complement system to enhance (i.e., complement) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body; it also promotes inflammation and attacks the pathogen’s cell membrane.

The complement system consists of a number of small proteins synthesized by the liver, which circulate in the blood as inactive precursors. When stimulated by one of several triggers, proteases cleave specific proteins to release cytokines (chemical messengers that communicate with cells) and activate the complement cascade, resulting in the 3 functions described above (clearing foreign material, inflammation, and cell membrane destruction).

Adaptive Immune System

The adaptive immune system is the body’s specific response to each individual antigen or potential pathogen encountered. This response begins when a dendritic cell (i.e., Langerhans cell) engulfs an antigen and then presents it to a lymphocyte. There are 2 types of lymphocytes: B lymphocytes (also known as plasma cells) and T lymphocytes. Lymphocytes are found primarily in lymph nodes but also throughout most of the body.

B Lymphocytes

B lymphocytes, also called B cells, are produced in the bone marrow and are responsible for the humoral (antibody) response. The humoral response occurs throughout the body, in the fluids between cells.

Each B cell has on its surface about 10,000 glycoprotein molecules, called membrane-bound antibodies or immunoglobulins (FIGURE 3). When a potential pathogen enters the body, membrane-bound antibodies will bind with the antigen (e.g., virus, bacteria, foreign protein). The antigen–antibody binding site is called an epitope and is very specific for just 1 protein, very much like a lock and key.

FIGURE 3. B-cell antibodies.

After a B cell becomes bound to the antigen at the epitope, the cell becomes activated, but only with the help of T helper cells (a safety feature, so the body does not attack just anything, including itself).

After activation, a B cell will start cloning itself. Some clones will become memory cells (which can hang around for 10 years or more, so if the same antigen/pathogen comes along, they are ready in large numbers to bind it and tag it for removal), and others will become effector cells (also called plasma B cells), which act as antibody factories, churning out as many as 2000 free-floating antibodies per second. These antibodies then bind to the pathogens, tagging them for destruction by phagocytosis (opsonization) (FIGURE 3).

When a B cell becomes activated (i.e., attached to the epitope on the antigen/pathogen), it will engulf the potential pathogen, digest it, and take some of the digested remains (a peptide chain made up of amino acids) and bind it to a protein of its own, forming an MHC type II. This is the phagocytosis we have already talked about, but these phagocytes are very specific, compared with other phagocytes (neutrophils), which are nonspecific. Helper T cells will activate the B cell, based on what they “think” of the MHC, and tell the B cell to clone itself into memory cells and effector cells (to produce those free-floating antibodies).

Before B cells are released from the bone marrow to perform the functions just described, they first go through “basic training and testing.” Any B cell that reacts to self proteins (almost all of the body’s proteins are available in the bone marrow for testing) will die. B cells that survive head to other parts of the body, including the lymph nodes. Unfortunately, this system is not foolproof and occasionally a B cell that reacts to self gets out into circulation. What happens then?

When a B cell that reacts to self escapes from the bone marrow, it still needs a specific T cell (with the same specific receptor) to find it and activate it before it can act against its own body, thereby acting as a backup safety mechanism.

T Lymphocytes

T lymphocytes, also called T cells, are produced in the bone marrow and mature in the thymus.3 As they mature, similar to B cells they undergo basic training and testing. Any T cell that fails testing and either binds too strongly, or not at all, to self MHC antigens, is destroyed (i.e., undergoes apoptosis). T cells that can recognize self and do not bind strongly enough to elicit a cytotoxic event are retained.⁴

T lymphocytes are activated after an antigen/pathogen has gotten inside a cell, at which time they trigger a cell-mediated response. There are 2 types of T cells: helper and cytotoxic.

Helper T Cells

Like B cells, the surfaces of helper T cells are covered in thousands of receptors, which are specific to each T cell. After binding to the presented antigen MHC II, a T cell is activated. Also like B cells, after activation, T cells clone themselves, with some becoming memory cells and some becoming effector cells.

Unlike B cells, however, T-cell effector cells do not make antibodies; instead, they release cytokines, which are chemical messengers that tell other cells to take specific actions (like ramping up the activities of B cells or starting an inflammatory or allergic cascade).

Cytotoxic T Cells

Cytotoxic T cells also have receptors all over their surface and are activated by binding to MHC I (MHC I is found in all nucleated cells in the body, as opposed to MHC II, which is found only in antigen-presenting cells). When a cell in the body is altered by a pathogen or neoplasia, it sends out a message via MHC I. This process is kind of like waving a flag that says, “There is something terribly wrong with me. Please kill me so that the rest of the body can survive.” Activated cytotoxic T cells clone into memory cells and effector cells. The effector T cells are the natural killer cells, which use proteins and enzymes to kill a cell when something has gotten inside that cell and it has become compromised in some way (i.e., neoplasia; virus).

The Immune System Gone Awry

In a perfect world, the immune system works very well. However, when B and T cells do not work as intended, the body can run into real trouble; the immune system can target the body itself rather than an invader. This results in immune-mediated or autoimmune diseases, which can affect different things in the body, including the skin. Immune-mediated diseases result from abnormal activity of the immune system. Autoimmune diseases are a subset of immune-mediated diseases, the result of the immune system overreacting and attacking the body itself. Fortunately, this does not happen very often! There are a number of autoimmune skin diseases that may occur in our veterinary patients, but most of these are rare. However, a few (pemphigus, lupus erythematosus, and vasculitis) occur more commonly, and we will focus on those.⁵

Pemphigus Complex

This complex of diseases includes pemphigus foliaceus, pemphigus erythematosus, pemphigus vulgaris, and pemphigus vegetans. These are vesiculobullous (blistering) and pustular disorders characterized by acantholysis (breakdown of cellular adhesions). The immune system, for various and often unknown reasons, starts to produce antibodies against parts of the desmosomes (the bridges that connect adjacent epithelial cells). The antibodies produced by the subtypes of pemphigus are directed against different antigens of the desmosomes, which determines the location of the vesicles/pustules and the various clinical signs. After the antibody is bound to the part of the desmosome, the antigen–antibody complex triggers intracellular reactions, leading to the release of plasminogen activators, which subsequently cause the conversion of plasminogen to plasmin. The production of plasmin causes disruption of the desmosome attachments and therefore loss of keratinocyte adhesion. This loss of adhesion between adjacent cells is called acantholysis.⁶  The resulting acantholytic cells are large, round epithelial cells with a large, dark-staining nucleus (FIGURE 4); they occur most often as single cells or in rafts of a few cells still partially joined together, in vesicles or pustules, formed by the destruction of the intercellular connections.⁷

FIGURE 4. Acantholytic keratinocytes (arrows) in a sea of neutrophils.

The immunopathogenesis of all diseases in the pemphigus complex seems to be the same, but the target proteins vary according to the type of pemphigus. Therefore, location of the bullae or separation within the epidermis differs; for example, the bullae of pemphigus foliaceus are more superficial than those of pemphigus vulgaris.⁸

In dogs, the most common autoimmune disease is pemphigus foliaceus (FIGURE 5). Pemphigus erythematosus is considered a mild and benign variant of pemphigus foliaceus because its lesions affect only the head (nose, face, and ears) (FIGURE 6). Hallmarks of pemphigus vulgaris are vesicles, erosions, and ulcers of the oral cavity and mucocutaneous junctions (FIGURE 7). Pemphigus vegetans is an extremely rare and milder variant of pemphigus vulgaris; it is distinguished clinically from other autoimmune diseases by production of lesions that are vegetative (proliferative) rather than pustular, vesicular, or ulcerative.⁵ All forms of pemphigus seem to be exacerbated by UV light.

FIGURE 5. Yellow crusts on a dog with pemphigus foliaceus.

FIGURE 6. Depigmentation of the nasal planum on a dog with pemphigus erythematosus.

FIGURE 7. Vesicles, erosions, and ulcers on mucous membranes of a dog with pemphigus vulgaris.

Pemphigus foliaceus lesions usually start on the face and pinnae, then appear on the feet (crusting and sometimes fissuring of the footpads). If the disease is not treated, lesions can also appear in the inguinal region and become multifocal or generalized. Pustules are large (spanning more than 1 hair follicle) and fragile, resulting in dry, yellow to brown crusts (FIGURE 5). Other lesions include erythema, scaling, alopecia, and epidermal collarettes. Lesions are often symmetric and include the head, which helps to differentiate pemphigus foliaceus from pyoderma. Depigmentation of the nasal planum (FIGURE 6) and footpads is common, as is waxing and waning of symptoms such as lethargy and anorexia. Pemphigus foliaceus is most common among Akitas, chow chows, cocker spaniels, dachshunds, and Labrador retrievers. Most patients are middle aged.⁹ The diagnostic procedure of choice is skin lesion biopsy, preferably of intact pustules, which enables the histopathologist to see the entire disease process; crusted lesions are not as telling. Simple in-house cytology taken by performing impression smears from lanced pustules or lifted crusts will reveal a sea of neutrophils with acantholytic keratinocytes. Eosinophils are also often seen.

Lupus Complex

In terms of lupus, animals are much more fortunate than people because lupus rarely produces systemic diseases in dogs.¹⁰ Genetic factors seem to play a role; breeds that are predisposed to lupus include collies, Shetland sheepdogs, German shorthaired pointers, Siberian huskies, and Brittany spaniels.

Discoid Lupus Erythematosus

One of the more frequently encountered autoimmune skin disorders of dogs is discoid lupus erythematosus. In patients with this disease, lesions can start as areas of depigmentation or erythema on the nasal planum (FIGURE 8) or footpads (FIGURE 9) that slowly progress to loss of the normal cobblestone appearance as plasma cells take over and actually push structures apart. Eventually, erosions, ulcers, and crusts develop. The area most commonly affected is the nasal planum, although lesions can extend up to the dorsal and lateral part of the haired muzzle. Without treatment, the alar wings will erode away. Scarring may occur in severe and chronic cases. Lesions have also been noted on the eyelids, lips, foot pads, and concave surface of the pinnae and in the oral cavity. Minor trauma to the nasal planum may trigger profuse hemorrhage. Sunlight exacerbates the lesions and may play a role in the pathogenesis of discoid lupus.¹¹ The diagnostic procedure of choice is skin lesion biopsy, preferably of areas that are graying, because histopathologic findings will be most fruitful in areas where depigmentation is actively going on. Any fully depigmented areas should be avoided because the depigmentation process has finished. Ulcerated lesions (deep erosions that extend all the way to the basement membrane) should also be avoided because they destroy the dermal-epidermal junction, which is the site of active disease.

FIGURE 8. Nose of a dog with discoid lupus erythematosus

FIGURE 9. Footpad of a dog with discoid lupus erythematosus.

Systemic Lupus Erythematosus

Dog breeds that are predisposed to systemic lupus are collies and Shetland sheepdogs. Systemic lupus affects multiple organs, including the skin for 40% to 50% of affected dogs. Systemic lupus is characterized by production of a variety of autoantibodies that form circulating immune complexes (FIGURE 10). These complexes can become “stuck” in different parts of the body, including organs. Signs and symptoms are often nonspecific and can wax and wane. Cutaneous signs associated with systemic lupus include ulcerative stomatitis, mucocutaneous erosions and ulceration, foot pad ulceration, seborrhea, panniculitis, urticaria, and purpura (bleeding into the skin manifested as petechiation and/or ecchymosis). Noncutaneous signs include polyarthritis, fever, glomerulonephritis, hemolytic anemia, thrombocytopenia, polymyositis, neurologic abnormalities, pleuritis, myocarditis, and lymphedema.¹²

FIGURE 10. Formation of an immune complex.

Vasculitis

Vaculitis is inflammation of blood vessels, which can result from physical trauma but most often results from an immune response to an infection or a drug reaction (including vaccines). Breeds that are predisposed to vaccine reactions include poodles, silky terriers, Yorkshire terriers, Pekingese, and Maltese.¹³ Histopathologically, the inflammatory response targets blood vessel walls, leading to destruction and ischemic changes, which in turn affect surrounding tissues. Vasculitis can involve just the skin but can be systemic. Although the disease process is not fully understood, theories include circulating immune complex formation and deposition in the vessel wall (type III hypersensitivity, in which the immune complex “clogs things up”) and direct binding of antibodies to the vessel wall antigen (type II hypersensitivity).

Clinical findings include erythema, plaques, scaling, alopecia, and purpura (FIGURE 11). Diascopy is a simple and helpful method for differentiating between erythema and ecchymosis. Also seen are ulcers, wheals, nodules, dependent edema, acrocyanosis, panniculitis (if deeper vessels are involved), and even tissue necrosis. Lesions are found on the distal extremities (including tail tip, ear tips, nail beds, footpads, nose, prepuce, scrotum) and pressure points. Systemic disease (e.g., hepatopathies, glomerulonephritis, synovitis–arthritis, gastroenteritis, pleuritis/pericarditis) may be a consequence of the vasculitis and/or of the underlying disease (e.g., anemia and/or thrombocytopenia of systemic lupus).

FIGURE 11. Dog with vasculitis.

Putting the Pieces of the Puzzle Together

All of the conditions described here can look similar to pyoderma, especially mucocutaneous pyoderma around the nasal planum, alar wings, and periocular region (FIGURE 12). TABLE 1 contains tips to help you distinguish between immune-mediated and infectious conditions.

FIGURE 12. Dog with mucocutaneous pyoderma.

In addition, look for any possible triggers in your patient’s history (e.g., vaccination, drugs, illness, seasonality, or changes in diet).¹⁴ Patient history should be thorough and include a timeline for clinical signs, response to medications, progression of lesions, and any other clinical signs such as fever, loss of appetite, or decreased activity. Paying attention to your patient’s history and clinical signs should help you recognize immune-mediated or autoimmune disorders.