Immunology and Skin in Health and Disease

Infectious Immunity: Part I. Examples of Bacterial Immunity

Staphylococcus aureus is a prevalent human skin commensal and pathogen that can cause superficial skin infections (impetigo and exacerbation of atopic dermatitis), infection of the hair follicle (folliculitis and furunculosis), as well as deep infections (ecthyma and abscesses). Like most other bacterial infections of the skin, these conditions are characterized clinically by tender, red, inflamed pustules and abscesses that form as a result of cytokine expression, neutrophil recruitment, and an epidermal response, including keratinocyte proliferation and production of antimicrobial peptides. Twenty percent of the population is colonized with S. aureus, and infections like those described above are quite common.

Methicillin-resistant S. aureus (MRSA) is a particularly recalcitrant infection due both to its antibiotic resistance as well as multiple virulence factors (a component of a pathogen that permits infection and survival; can be protein, lipid, carbohydrate, or nucleic acid) (reviewed by Foster 2005). S. aureus is a Gram-positive coccus, which has an outer cell wall. Innate immune receptors and PRRs important in the detection of Gram-positive bacteria include Toll-like receptor 2 (TLR-2), and mannose-binding lectin (MBL), which are capable of detecting the sugars and lipids that comprise bacterial cell walls. As described in detail above, ligation of PRRs associated with skin-resident immune cells induces activation and maturation of DCs, keratinocyte proliferation and antimicrobial peptide production, and the production of cytokines and chemokines to promote the recruitment of neutrophils and macrophages to the site of infection. Once in the skin, neutrophils and macrophages phagocytose and destroy the bacteria. As mentioned above, phagocytosis is aided by opsonization with antibodies and the binding of complement. Once bacteria are taken into the phagosome, it fuses with the lysosome resulting in acidification, activation of proteases, and production of reactive oxygen species, all of which are capable of breaking down the pathogens. This process also results in the generation of antigens, which can be presented on HLA II to activate the adaptive immune response. During this process, some macrophages and DCs will migrate to the draining lymph node to activate T and B cells via the HLA II–antigen complexes for initiation of the adaptive immune response. Activation of T cells and T_H17 skewing seems to be particularly important for antibacterial immunity. This is attributable to the functions of T_H17-associated cytokines: IL-17, 22, and 23 can promote thickening of the epidermis, production of antimicrobial peptides, and recruitment of neutrophils, which further enhances bacterial clearance.

S. aureus has developed several mechanisms to avoid the host immune response. It can avoid phagocytosis through the virulence factors Protein A (interferes with IgG binding to its FcγR), ClfA (promotes coating with fibrinogen, which outcompetes the binding of opsonins including complement), and capsule formation (promotes biofilm formation via polysaccharide intercellular adhesion), which inhibits complement and antibody binding. It can also prevent phagolysosomal fusion via the virulence factor SarA, thereby evading death and surviving within the immune cells themselves. Inside the host phagocytes, S. aureus can also scavenge free radicals via superoxide dismutases. The unique structure of its wall is resistant to degradation by lysozyme. These factors may in part explain why it is so difficult to induce good adaptive immune responses to S. aureus, as there could be less efficient antigen generation and presentation.

S. aureus produces the chemotaxis inhibitory protein of staphylococci (CHIPS), which can bind to and inhibit chemoattractant receptors on the surface of neutrophils. It also produces Eap, a protein that disrupts LFA-1 and ICAM-1 interactions that are required for neutrophils to adhere to endothelial cells and transmigrate into the skin (see also Box 2). The bacteria are also capable of preventing complement fixation through production of a Staphylococcus complement inhibitor (SCIN), Efb, or through Staphylokinase, an enzyme that promotes degradation of complement, antibodies, and clots. As mentioned above, complement is important not only for phagocytosis of bacteria, but also for neutrophil chemotaxis. By inhibiting complement fixation, therefore, the bacteria are not only avoiding complement-mediated lysis and opsonization, but also potentially reducing the number of neutrophils that are recruited to the skin by the complement proteins C3a and C5a. S. aureus is capable of expressing nucleases, which can cut neutrophilic NETs comprised of DNA discussed above, in addition to lipases and proteases, which supports their dissemination.

Another way that S. aureus can avoid the host immune response is by invading epithelial and endothelial cells and living inside them in a semi-dormant state. Intracellular pathogens usually require cell-mediated immunity to clear infection. However, S. aureus has also developed mechanisms to evade T cell and other leukocyte responses, namely through production of toxins and superantigens. The α-toxin is capable of inserting into host membranes and multimerizing to form a pore, much like the way complement can form a pore in bacterial cell walls. Other toxins include the Panton–Valentine leukocidin (PVL), which can lyse leukocytes, and the leukocidin D/E, leukocidin M/F, and the γ-hemolysin (Hlg), which can lyse erythrocytes and leukocytes. Recurrent furunculosis and other conditions have been associated with PVL expression by S. aureus. S. aureus also produces one of the best-characterized superantigens, which nonspecifically activates T cells via strong binding of both the MHC II and the T-cell receptor. Toxic shock syndrome toxin-1 (TSST-1, which can initiate tampon-associated toxic shock syndrome) prevents the generation of normal T-cell responses against the bacterium and also affects the ability to generate antibody responses by B cells, which often need T cell help for appropriate class switching and activation.

In light of all of the ways in which S. aureus can evade immune responses, it is easy to see why drug-resistant strains pose a threat. Immunocompromised patients are especially vulnerable (see Box 3), making it of utmost importance to understand skin immunity to bacteria.

Infectious Immunity: Part II. Examples of Viral Immunity

Antiviral immunity largely depends on NK and CTL responses. Both NKs and CTLs kill their targets via perforin/granzyme-induced apoptosis. The inflammatory response to most viral infections of the skin consists of minimal inflammation and symptoms caused by the targeted destruction of virally infected cells and therefore usually lack redness, swelling, or pus that are characteristic of bacterial or fungal infections. T_H1-type cytokines are important for antiviral immunity because they drive CTL responses and antiviral mechanisms through production of IFN-γ. We will discuss human papilloma virus (HPV) as an example of antiviral immunity in the skin. HPV is the most common STD; it is estimated that 50% of sexually active men and women get infected. The majority of people who contract HPV clear the infection within 2 yr, and not everyone that has HPV will develop cancer, as this is strain dependent. In this section, we will highlight concepts of antiviral immunity and ways in which HPV can subvert the host immune response.

More than 70 different strains of HPV exist. HPV belongs to the papillomaviridae family of nonenveloped DNA viruses. HPV productively infects keratinocytes, and takes over the cellular machinery to manufacture progeny viruses. The HPV replication cycle is tied to keratinocyte differentiation, in which HPV early proteins (“E” 1–7) are produced in undifferentiated keratinocytes and late proteins (“L” 1 and 2), which are involved in capsid formation, are produced in more superficial cells to promote sloughing of virus. Some HPV strains can be transmitted sexually and cause genital warts, whereas some can cause warts on other parts of the skin. Different HPV strains are adapted to infect specific anatomic locations. For example, strain 1 usually infects the soles of the feet, strain 2 the palms of the hands, strains 6 and 11 are associated with genital warts, and strains 16 and 18 can cause cervical cancer. Recently, two vaccines were developed against HPV: Gardasil (types 6, 11, 16, and 18) and Cervarix (types 16 and 18) in hopes of preventing most cervical cancers (90% contain HPV DNA).

HPV produces proteins E6 and E7 that inhibit host p53 and Rb, respectively, which normally are involved in sensing DNA damage and repair mechanisms to halt cell-cycle progression. This is accomplished via ubiquitin-mediated proteasomal degradation. P53 and Rb are known as the “guardians of the genome” because the DNA damage-sensing mechanism is important for cells to maintain the health of the genome and to avoid improper growth. Because viruses need to use the host cell machinery to replicate, overriding these proteins allows them to replicate more efficiently. A byproduct of this is the hyperproliferation of keratinocytes that characterizes a wart. HPV can also avoid IFN-mediated antiviral responses through E7, which can bind to and inhibit the promoters of type-I IFN-related genes. Treatment with IFN-α can be used for genital warts, although patients with higher E7 levels tend to respond less well than patients with low E7. E6 can down-regulate IL-18 expression, which is important for the generation of T_H1 and CTL responses.

Productive antiviral immunity depends on NK cell responses, CTL responses, and antibody production. NK cells look for the presence or absence of self HLA I on the surface of cells, whereas CTLs respond to specific HLA I–peptide complexes. To avoid detection by CTLs, many viruses have developed the ability to down-regulate HLA I. For example, the E5 protein of HPV is capable of down-regulating HLA I expression via inhibition of tapasin and HLA I promoter binding by transcription factors. Yet even though the chance of activating a CTL is decreased by E5, an NK cell could still kill an HPV-infected target cell. NK cells receive activating signals through killer activating receptors (KARs), whereas inhibitory signals are transmitted through killer inhibitory receptors (KIRs), which detect presence of HLA I on the cell’s surface. Therefore, it is the balance of positive and negative signals that the NK cell receives that will determine whether or not it will kill the target cell. However, not many NK cells are recruited to sites of HPV infection, as the virus has devised other mechanisms to subvert inflammatory responses. Part of this is because of the sequestration of the virus inside primarily differentiated keratinocytes, which are located high in the epidermis. HPV induces the recruitment of CD4⁺CD25⁺FoxP3⁺ Tregs via CCL17 and CCL22 production by LHC and macrophages within the wart. Consistent with their function discussed above, these Tregs can dampen inflammation and promote viral survival. In addition, Tregs specific for HPV antigens have been found in cervical cancer patients (see Box 6).

Antibody responses to viruses like HPV help prevent initial infection or spread of infection via neutralization of binding of the virus to the host cells. Yet the availability of HPV antigens during infection is often low owing to the fact that, unlike other viruses, HPV does not induce lysis of its target cells to allow for release of virions thereby producing free antigens. Additionally, the L proteins are most immunogenic but are primarily produced in superficial keratinocytes, thereby allowing the virus to avoid detection by most LHC, which reside closer to the basement membrane. Therefore, antibody responses to HPV are often delayed and inadequate. Some LHC and other APCs are able to take up HPV antigens either through phagocytosis of cellular debris or possibly through exosomes, which are nanometer-sized structures secreted by the cell. However, HPV infection is not a highly inflammatory process, and therefore lacks stimulation of APCs to mature, secrete proinflammatory cytokines or promote effector T-cell activation. Several HPV proteins mimic host proteins and therefore can be tolerogenic. (Subversion of host immunity by HPV is nicely summarized by Tindle [2002].)

Infectious immunity: Part III. Examples of fungal and yeast immunity

Antifungal immunity relies heavily on the innate immune system, and protective immunity depends on both T_H1 and T_H17 responses as well as antibody production. Like S. aureus, Candida albicans colonizes much of the population, but is primarily pathogenic in immunocompromised patients, where disease incidence is 24 cases per 100,000. Treatments for Candida are antifungal drugs, such as miconazole and fluconazole, which inhibit formation of fungal cell membranes. Several antifungal vaccines have made it to phase I clinical trials, however achieving both efficacy and safety has proven difficult.

PRRs that are important for recognition of Candida include TLRs 2, 4, and 6, as well as lectin-like receptors including dectins, galectins, DC-SIGN and the mannose receptor. All of these PRRs recognize sugar and lipid components of the fungal cell wall, such as β-glucan, zymosan, and chitin. Complement receptor 3 (CR3) is important for recognizing opsonized Candida and other pathogens. TLR-9, an intracellular PRR, is important for recognition of fungal DNA, which is hypomethylated compared with mammalian DNA (recognition of Candida is summarized by Netea et al. 2008). Skin-resident macrophages and DCs use these PRRs to detect Candida, and initiate the recruitment of neutrophils and monocytes via cytokine and chemokine production. Recruited populations of neutrophils and monocytes phagocytose Candida and kill it via generation of reactive oxygen species. Extracellular killing is also induced, although the mechanism for this is not yet known.

As described above, skin-resident LHCs have been reported to initiate T_H17 cell responses. Interestingly, ligation of different PRRs generates different T_H profiles: ligation of the mannose receptor usually results in IFN-γ production and T_H1 responses, chitin recognition and fungal DNA recognition results in IL-4 and IL-13 production and T_H2 responses, and hyphae recognition by dectin 1 results in IL-17 production and T_H17 responses. Treg responses can also be generated through tolerogenic DC populations and TRIF-dependent signaling downstream of some PRRs. Most of these associations have been determined using PRR knockout mouse models of Candidiasis. However, little is known about how these mixed T-cell responses ultimately influence the host’s ability to clear the pathogen, although it seems that early generation of Treg responses allows Candida to subvert host immunity. It is possible that confusing the immune system by inducing these mixed T-cell responses also dampens host immunity owing to a lack of positive-feedback loops. One possible mechanism for this differential induction of immune responses would be the morphological changes that occur when Candida transitions from yeast to hyphae, which results in differences in bioavailability of PAMPs from the cell wall. Understanding this modulation of DCs by different fungal epitopes is important for the design of effective antifungal vaccines.

Infectious Immunity: Part IV. Examples of Parasite Immunity

Immunity against parasites is mediated by a mixture of innate and adaptive immune responses that rely on IgE, granulocytes, and T_H2 cells. Parasites present challenges to the immune system because of several factors, including their size and complexity, migration to different tissues within the body, and ability to subvert the host immune response. These immune evasion mechanisms have made it notoriously difficult to develop vaccines against parasites. We will discuss skin immune responses to the hookworm as an example of antiendoparasite immunity (see Box 7 for a note on ectoparasites). Hookworms are nematodes that belong to the family Ancylostomatidae, and infect approximately 20% of the world population. The larvae burrow into the skin, often through the feet that come into contact with contaminated soil or water. As they mature, they travel through the blood to the lungs and eventually the intestines, where they feed off of blood and reproduce. Hookworm eggs are secreted in feces, and embryos develop and hatch in the soil or water where they consume bacteria until they develop into the infective worm stage, L3, thus completing the life cycle (reviewed by Loukas and Prociv 2001).

On entering the skin, L3 hookworm larvae shed their outer cuticle and begin expressing enzymes that permit their movement through tissues. Cuticle or sheath antigens can be taken up by APCs and presented to T and B cells. Initially following skin invasion, zoonotic species elicit inflammatory responses that cause a creeping eruption or ground itch, whereas anthropophilic species can do so silently. Antibody responses have been detected to the cuticle as well as the exsheathing fluid, and it has been suggested that this allows the worm to misdirect the immune response, similar to countermeasure decoys to distract a heat-seeking missile. Antibody responses to fluid and cuticle proteins may be used clinically as a diagnostic tool for detecting infection. Although T-cell responses seem to be weak and their exact specificities are unknown, T_H2-cell responses against hookworms result in production of IL-4 and IL-13, which induce B-cell class switching to IgE. Interleukin-5 (IL-5), a major eosinophil survival and activation factor, is also produced by T_H2 cells. Eosinophils are recruited to sites of infection and are major players in antiparasite immunity. They bind IgE-opsonized larvae via the FcεR, causing them to degranulate. Enzymes, and the reactive oxygen species that they release, degrade larvae. Once the larvae matures into an adult worm in the intestine, immune responses seem to become elevated most likely in response to the greater availability of worm antigens. Coinciding with this, peripheral eosinophilia is often seen in patients with hookworm infections. Tissue-resident mast cells also degranulate on encountering a larvae or worm, which may result in the recruitment of more eosinophils. Their mechanism of activation is slightly different from that of eosinophils in that they may have IgE preloaded in their FcεRs. IL-9 seems to be important for mast-cell activation and production of proteases.

In addition to misdirecting antibody responses to their cuticle, hookworms have developed several other mechanisms to subvert the host immune response. They produce a neutrophil inhibitory factor protein (NIF), which interferes with neutrophil recognition of opsonized parasites; C-type lectins that mimic those of the host, which interfere with immune recognition and coagulation; metalloproteinases and peptides that interfere with coagulation and permit feeding; cysteine proteases that cleave Igs and the low-affinity IgE receptor; and aspartic proteases, which help them digest hemoglobin but also may be involved in cleaving Igs and complement. They also produce protease inhibitors and antioxidants that help them withstand the effects of degranulation by eosinophils and mast cells. Hookworms also produce acetylcholinesterases, which are thought to both inhibit gut peristalsis and interfere with immune function.

Improper Immune Responses: Part I. Allergy

Allergy is an improper immune response to an otherwise innocuous antigen. The incidence of allergic disease is rising in developed countries, and treatments cost $400 million annually in the United States alone (see Box 8). Allergic contact dermatitis occurs following chemical or environmental exposure, resulting in generation of neoantigens via haptenization of self-molecules (reviewed by Kaplan et al. 2012). Haptens themselves can cause oxidative stress in keratinocytes, resulting in release of reactive oxygen species and danger signals, such as ATP. Neoantigens produced in response to hapten exposure, such as byproducts of hyaluronic acid degradation, can activate TLRs, resulting in production of proinflammatory cytokines by skin-resident immune cells. Studies in mice have indicated that recognition of neoantigens is mediated by TLR-2 and/or TLR-4 in IL-12-dependent and -independent mechanisms. It is also thought that NLRs and the inflammasome are capable of recognizing haptens and neoantigens, although many ligand-receptor partners have yet to be determined. Repeated exposure induces sensitization and subsequent type IV hypersensitivity (see Box 9). This response is characterized by an influx of T cells to the skin, resulting in tissue damage and an inflammatory eruption.

Tissue penetration of haptens is crucial for induction of allergic contact dermatitis. Close to 3000 compounds have been discovered that are capable of inducing contact dermatitis. Small molecular weight compounds can diffuse through the epidermis, although disruption of the barrier function of keratinocytes is thought to speed up the sensitization process (see Box 1). Examples of compounds that can elicit allergic contact dermatitis include nickel, which is the most common contact allergen and can bind directly to TLR-4 (see Box 10 and Schmidt et al. 2010), and the dust mite allergens Der p 2 and Der f 2, which are homologs of the endogenous TLR-4-binding protein MD2. Dust mites, or Dermatophagoides subspecies, consume sloughed keratinocytes, and are often found in clothing, bedding, and on the skin. Dust mites often cause allergic responses attributable to the type of immune responses they elicit: IgG and IgE responses confer immunity but also hypersensitivity reactions. Tissue-resident mast cells also play a role in skin allergy, caused by their ability to degranulate after their surface-loaded IgE is cross-linked on an allergen encounter. Whereas systemic and topical steroids are sometimes used to manage acute symptoms, the preferred treatment for contact dermatitis is avoidance of the allergen.

Improper Immune Responses: Part II. Autoimmunity

Autoimmunity results when the immune system targets self-tissues, resulting in destruction, and, potentially, organ failure. There are checkpoints to prevent the immune system from targeting self-tissues; and, therefore, autoimmune disease is believed to require multiple hits that deactivate those checkpoints (similar to the multihit hypothesis of cancer development). These mechanisms include central tolerance through deletion of autoreactive T and B cells in the thymus (see Box 11), peripheral tolerance through the action of CD25⁺ Tregs (see Box 4), production of anti-inflammatory cytokines, such as IL-10 and TGF-β, and down-modulation of proinflammatory cytokine production by ligation of certain PRRs on innate and tissue-resident immune cells, such as the phosphatidyl serine receptor on macrophages, which aids in uptake of apoptotic cells in a physiologic context. Because autoimmunity is a destructive process and does not appear to be beneficial for survival, these responses likely evolved as overzealous anti-infectious or antitumor responses. For example, Japanese have a very low incidence of psoriasis compared with U.S. or European populations, whereas their risk for tuberculosis is much higher, suggesting that their genetic makeup puts them at low risk for psoriasis but high risk for tuberculosis. IFIT1 is a component of interferon signaling, and is a risk allele for type I diabetes, but the high-risk allele for diabetes is protective against coxsackie viral infection, suggesting that this allele evolved to protect from infection. Native Americans were devastated by tuberculosis infection on arrival of Europeans—the descendants of those who survived now have a very high risk for rheumatoid arthritis, suggesting that tuberculosis survivors possessed aggressive immune responses that now promote autoimmunity. These examples support the hypothesis that autoimmunity developed as a consequence of evolving potent anti-infectious responses. Therefore, we will categorize autoimmune responses accordingly. In addition to improving our understanding of pathogenesis, an advantage to thinking about autoimmunity in this way is that treatments used to interfere with autoimmunity are likely to increase the risk for infections controlled by that response.

In this section, we will discuss both T-cell-driven autoimmune disease and B-cell-driven autoantibody-mediated disease in the context of improper antiviral/tumor, or antibacterial/fungal immune responses.

Antibacterial-Like Autoimmunity

Psoriasis, which afflicts 2%–3% of the world population, is a highly inflammatory disease of the skin that presents with pruritus, pain, erythema, occasional pustules, and thickened scales. Histologically, it is characterized by epidermal acanthosis, vascular proliferation, and a significant inflammatory infiltrate consisting of neutrophils, T cells, DCs, and other populations. Keratinocytes produce significant levels of antimicrobial peptides, and the cytokines IL-23, IL-17, IL-6, and IL-22 appear to play a prominent role in pathogenesis. These characteristics mirror those seen in an antibacterial response and, in fact, lesions of psoriasis rarely become superinfected, unlike in atopic dermatitis. This resistance to infection is probably caused by this overzealous antibacterial-like response.

Treatment for psoriasis includes local, general immunosuppressive medications like topical steroids and calcineurin inhibitors, systemic general immunosuppressants like cyclosporine A and methotrexate, as well as newer, more targeted systemic biologic medications like TNF-α inhibitors, p40 (a component of IL-23) inhibitors, and IL-17 inhibitors. Although these treatments are likely to have improved safety profiles over more general immunosuppressants, they still have rare, but predictable, side effects based on their ability to interfere with the antibacterial response, including an increased incidence of bacterial and fungal infections. A more detailed discussion concerning psoriasis and its treatments is addressed in the literature.

Antiviral-Like Autoimmunity

Vitiligo is an autoimmune disease of the skin that results in the loss of melanocytes from the epidermis, which can be quite psychologically devastating for patients. It affects ∼0.5% of the population worldwide, without preference for race or gender, and targets all areas of the skin, with a preference for the face and genitals greater than hands and feet greater than trunk and proximal extremities. The patchy depigmentation is typically symmetrical except in the case of segmental vitiligo, in which unilateral depigmentation typically remains localized and limited by the midline. Segmental vitiligo affects ∼5% of all vitiligo patients but is responsible for a larger component of childhood vitiligo, affecting ∼20%. Patients with vitiligo are typically asymptomatic, with only ∼20% complaining of mild itching in lesional skin.

On physical exam, there is typically no erythema or scale, signs seen only in the rare inflammatory subtype. Histological examination may reveal a subtle infiltrate made up of CD4⁺ and CD8⁺ T cells in the absence of neutrophils or epidermal proliferation. Often, lesional skin contains few T cells. Because keratinocytes retain the pigment that they acquire from melanocytes as they differentiate through the layers of the epidermis until they are sloughed off, melanocyte destruction does not result in visible depigmentation until complete turnover of the overlying keratinocytes, a process that requires 14–48 d. During this time, destructive T cells likely migrate laterally through the skin to perpetuate disease, and therefore are not present once the depigmented epidermis becomes clinically visible. Thus, biopsy recommendations to “catch” an immune infiltrate include selecting perilesional skin up to 1 cm beyond the visible border, a slightly hyperpigmented region beyond the border, or better, an elliptical biopsy radiating outward from the lesion, including the border itself and up to 1 cm beyond.

Vitiligo is mediated by CTLs and IFN-γ production, reflecting a T_H1 immune response within the skin. Unlike some autoimmune diseases where it has been difficult to determine which antigens the autoreactive T cells are responding to, the TCR specificities in vitiligo have been determined for a number of peptides, including MART-1/Melan-A (melanoma antigen recognized by T cells), tyrosinase (an enzyme required for melanin production), and gp100 (also known as premelanosome protein, a transmembrane protein expressed on the surface of pigment-producing cells in the skin and eye). This clinical, histological, and mechanistic picture is similar to what is seen in response to a viral infection or antitumor response, in contrast to psoriasis. Consequently, attempts to treat vitiligo using anti-TNF-α inhibitors have been disappointing, and no other systemic therapies for vitiligo are widely available. Typical treatments for vitiligo include topical steroids and calcineurin inhibitors, as well as narrow-band UVB light therapy. New approaches to treatment will likely benefit from targeting IFN-γ and other components of the T_H1 inflammatory pathway.

Antibody-Mediated Autoimmunity

The skin is affected by a number of autoimmune diseases that are clearly mediated by antibodies. These diseases can be subdivided according to whether they are tissue specific, or tissue non-specific. Tissue-specific diseases are relatively straightforward, as the antibodies interfere with protein–protein binding, and the symptoms develop from a lack of protein function. Tissue-specific antibody-mediated autoimmune diseases of the skin include pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA, and others. Pemphigus vulgaris is mediated by antibody production against desmoglein 3, which is predominantly expressed in the basal epidermis and acts as a glue to hold keratinocytes together. The result is separation of the epidermis just superior to the basal keratinocyte layer, which then accumulates fluid and forms a bulla on the surface of the skin. In contrast, pemphigus foliaceus is mediated by desmoglein 1 antibodies, forming bullae in the superficial layers of the epidermis and mucosae, because of predominant expression of desmoglein 1 at that location. Because these diseases are primarily antibody mediated, they require little contribution from immune cells during the effector phase apart from the plasma cells that produce the antibodies. As mentioned above, despite being a B-cell-driven autoimmune disease of the skin, B cells are not typically found within the skin, but reside within the lymph nodes and bone marrow, secreting antibody into the blood stream, which is then delivered passively to the skin and sterically disrupts protein–protein binding. Consequently, there is little inflammation present within lesional skin, and topical immunosuppression has limited efficacy. Treatment is aimed at systemic general immunosuppression, including prednisone, mycophenylate mofetil, azathioprine, cyclophosphamide, and/or cyclosporine, which ultimately results in decreased antibody production. Recent studies suggest that rituximab, an antibody that targets B cells but not plasma cells, may be an effective treatment, so it is not yet clear exactly how it modulates this plasma cell-driven disease.

Tissue nonspecific antibody-mediated autoimmune diseases are best characterized by the connective tissue diseases. Lupus erythematosus is probably the best understood of these diseases, yet mechanisms of pathogenesis are far from clear. Autoantibodies in lupus appear to target self-proteins that are not limited to a specific tissue, unlike the tissue-specific diseases. Common targets include DNA, RNA, and their associated proteins. It is likely that necrotic cell death initiates the inflammatory response following release of nuclear contents, a process that is prevented during programmed cell death, or apoptosis. Sun exposure may contribute to pathogenesis through damage of keratinocytes and subsequent release of nuclear contents. Antibody–protein complexes form within the vasculature and precipitate onto small vessel endothelium in specific organs, including the skin, kidney, joints, and others. Therefore, inflammation may appear in any of these organs, resulting in a wide variety in clinical presentation and symptoms, even within the same individual. Recent data suggest that nuclear components act as self-DAMPs (see above) and initiate immune responses through TLRs and NLRs within the tissues. More research will be required to understand the detailed pathogenesis of these complex systemic diseases.

Malignancy

Proper immune responses to combat malignancy are similar to antiviral responses, often involving NK cells and CTLs, which are capable of killing altered-self cells. Often, tumors down-regulate HLA I expression and avoid CTL-mediate killing, yet they then become susceptible to NK cells. They are also often stressed because of hyperproliferation, and can present altered self-peptides on HLA I that can be recognized by CTLs. For in-depth discussions of malignancies of the skin, please refer to the chapters covering melanoma and cutaneous T-cell lymphoma.