13: Basic Principles of Immunologic Diseases in Skin (Pathophysiology of Immunologic and Inflammatory Skin Diseases) Flashcards
What is the role of haptens in allergic contact dermatitis?
Haptens are low molecular weight chemicals that, when repeated exposure occurs, can trigger an immune response by binding to endogenous proteins, leading to sensitization and subsequent allergic reactions.
What are the two major pathways involved in innate immunity related to allergic contact dermatitis?
- Inflammasomes: Activated by exposure to substances like urushiols and Cr2+, leading to the release of proinflammatory cytokines (IL1B, IL18, TNFa).
- Toll-like receptors: Such as TLR4, which binds nickel and Cr2+, resulting in the production of IL1B, IL18, and IFN.
What is the significance of CD8+ T cells in allergic contact dermatitis?
CD8+ T cells are the primary mediators of skin inflammation in allergic contact dermatitis. They accumulate in lesional and postlesional skin and can distribute to distant skin sites as resident memory T cells (TRMs).
What are some severe cutaneous adverse reactions (SCARs) associated with drug reactions?
Severe cutaneous adverse reactions include:
1. Stevens Johnson syndrome (SJS)
2. Toxic epidermal necrolysis (TEN)
3. Drug induced hypersensitivity syndrome (DiHS), also known as DRESS
4. Acute generalized exanthematous pustulosis (AGEP), which is less severe.
How does ethnicity influence genetic predisposition to drug reactions like SJS and TEN?
Ethnicity-dependent genetic predisposition includes:
1. Han-Chinese SJS/TEN:
- HLA B58:01 – allopurinol
- HLA B15:02 – carbamazepine
2. Asians DiHS/DRESS:
- HLA B13:01 – dapsone.
A patient presents with recurrent skin lesions after exposure to nickel. What molecular mechanisms are likely involved in this allergic contact dermatitis?
Nickel exposure activates Toll-like receptor 4 (TLR4), leading to the production of IL1B, IL18, and IFN. Additionally, CD8+ T cells mediate skin inflammation, and hapten-specific memory T cells are formed during sensitization.
A patient develops severe skin blistering after taking allopurinol. What genetic predisposition might explain this reaction?
The patient may have the HLA-B58:01 allele, which is associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Han-Chinese populations.
A patient with toxic epidermal necrolysis (TEN) is found to have HLA-B15:02. What drug might have triggered this reaction?
Carbamazepine is associated with TEN in patients with the HLA-B15:02 allele.
What are the phases involved in allergic contact dermatitis and their significance?
The phases involved in allergic contact dermatitis are:
1. Sensitization/Afferent Phase:
- Initiated after hapten exposure.
- Antigen presenting cells (APCs) are activated and migrate to draining lymph nodes.
- T cell expansion occurs, leading to the formation of hapten-specific memory T cells.
2. Elicitation Phase:
- Triggered by re-exposure to the hapten.
- Results in T cell mediated dermatitis, causing an inflammatory response.
How do Langerhans cells and dermal dendritic cells contribute to the immune response in allergic contact dermatitis?
Langerhans cells and dermal dendritic cells (DDCs) play distinct roles in the immune response:
- Langerhans Cells:
- Involved in contact hypersensitivity response (CHS).
- Express CD1a, which is the binding site for urushiol, but their role is inconclusive in ACD.
- Dermal Dendritic Cells (DDCs):
- Contribute to CD8+ T cell responses during antiviral responses.
- They are crucial mediators of skin inflammation in allergic contact dermatitis (ACD).
What are the severe cutaneous adverse reactions (SCARs) associated with drug reactions, and what are their genetic predispositions?
Severe cutaneous adverse reactions (SCARs) include:
- Stevens Johnson Syndrome (SJS)
- Toxic Epidermal Necrolysis (TEN)
- Drug Induced Hypersensitivity Syndrome (DiHS), also known as DRESS (drug reaction eosinophilia with systemic symptoms)
- Acute Generalized Exanthematous Pustulosis (AGEP), which is less severe.
Ethnicity Dependent Genetic Predisposition:
1. Han-Chinese SJS/TEN:
- HLA B58:01 – allopurinol
- HLA B15:02 – carbamazepine
2. Asians DiHS/DRESS:
- HLA B13:01 – dapsone.
What role do cytotoxic T cells play in SJS/TEN lesions?
Cytotoxic T cells are readily detected in SJS/TEN lesions and are considered pathogenic. In early SJS/TEN, CD8 T cells along the dermal-epidermal junction (DEJ) contribute to interface dermatitis and keratinocyte apoptosis, similar to findings in erythema multiforme (EM).
What are the hallmark features of Drug-Induced Hypersensitivity Syndrome (DiHS) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)?
DiHS/DRESS is characterized by maculopapular or morbilliform lesions, lymphadenopathy, and atypical lymphocytes in peripheral blood. A hallmark feature is peripheral eosinophilia, along with potential reactivation of viruses such as HHV-6, HHV-7, EBV, and CMV due to the expansion of regulatory T cells.
What genetic mutations are associated with Netherton Syndrome and its clinical features?
Netherton Syndrome is associated with a mutation in SPINK5, a cell surface protease inhibitor, leading to increased activity of serine protease. This results in compromised barrier function of the stratum corneum and is characterized by eczematous dermatitis and elevated IgE levels in patients.
How does Job Syndrome affect immune response and what are its clinical implications?
Job Syndrome, also known as Hyper IgE Syndrome, is characterized by dermatitis and impaired TH17 response, leading to increased susceptibility to Staphylococcus aureus infections. It is associated with a loss of function mutation in STAT3, which is also identified in classic atopic dermatitis (AD).
What is the significance of Staphylococcal dysbiosis in Atopic Dermatitis?
Staphylococcal dysbiosis correlates with the activity of Atopic Dermatitis (AD). Treatments such as bleach baths can help control AD by modifying the cutaneous microbiome, and topical steroids can reverse microbial dysbiosis even without antibacterial treatment.
What are the effects of Dupilumab and Tofacitinib in the treatment of Atopic Dermatitis?
Dupilumab is an IL-4 and IL-13 blocker that has shown effectiveness in phase 3 trials for Atopic Dermatitis. Tofacitinib, a JAK inhibitor, has demonstrated improvements in eczema area and severity index (EASI) in phase IIa trials for AD.
A patient with atopic dermatitis shows elevated IgE levels. What genetic mutation might contribute to this condition?
A loss-of-function mutation in the FLG gene or SPINK5 polymorphisms could contribute to elevated IgE levels and compromised skin barrier function.
A patient with drug-induced hypersensitivity syndrome (DiHS) shows peripheral eosinophilia and liver damage. What viral reactivation might be involved?
Reactivation of HHV-6, HHV-7, EBV, or CMV may be involved, with circulating EBV-specific CD8+ T cells potentially causing liver damage.
A patient with atopic dermatitis is unresponsive to anti-IgE therapy. What alternative biologic might be effective?
Dupilumab, an IL-4 and IL-13 blocker, has shown efficacy in treating atopic dermatitis.
A patient with fixed drug eruptions (FDEs) experiences recurrent lesions at the same site after drug re-exposure. What immune cells are responsible?
CD8+ resident memory T cells (TRMs) mediate the interface dermatitis seen in FDEs.
A patient with Stevens-Johnson syndrome (SJS) shows CD8+ T cells along the dermoepidermal junction. What is the pathological mechanism?
CD8+ T cells mediate interface dermatitis and keratinocyte apoptosis, contributing to the lesions in SJS.
A patient with Netherton syndrome has elevated IgE levels. What genetic mutation is responsible for this condition?
A mutation in the SPINK5 gene, which encodes a cell surface protease inhibitor, leads to increased serine protease activity and compromised skin barrier function.
A patient with atopic dermatitis undergoes bleach baths. What is the therapeutic mechanism?
Bleach baths control atopic dermatitis by modifying the cutaneous microbiome and reducing Staphylococcal dysbiosis.
A patient with drug-induced hypersensitivity syndrome (DiHS) develops autoimmune sequelae. What is the underlying immunological mechanism?
Breakdown of peripheral tolerance leads to immunological abnormalities, resulting in conditions like Hashimoto thyroiditis, SLE, or type 1 diabetes.
A patient with atopic dermatitis shows increased CCL17 (TARC) levels. What immune response is this associated with?
Increased CCL17 levels are associated with a type 2 immune response.
A patient with atopic dermatitis is treated with Tofacitinib. What is the expected outcome?
Tofacitinib, a JAK inhibitor, improves the eczema area and severity index (EASI) in atopic dermatitis.
A patient with atopic dermatitis shows Staphylococcal dysbiosis. What treatment can reverse this without antibacterial therapy?
Topical steroids can reverse microbial dysbiosis in atopic dermatitis.
A patient with atopic dermatitis is unresponsive to Omalizumab. Why might this be the case?
Omalizumab, an anti-IgE monoclonal antibody, is not effective in atopic dermatitis despite its efficacy in asthma and urticaria.
What role do cytotoxic T cells play in SJS/TEN lesions and how do they differ in DiHS/DRESS?
In SJS/TEN lesions, cytotoxic T cells, particularly CD8 T cells, are readily detected and are pathogenic, contributing to interface dermatitis and keratinocyte apoptosis. In contrast, they are less prominent in DiHS/DRESS cases.
How do Fixed Drug Eruptions (FDEs) manifest and what is their underlying mechanism?
Fixed Drug Eruptions (FDEs) are characterized by CD8+ T cell mediated interface dermatitis. The lesions recur in previously involved locations after systemic drug administration due to clones of drug-reactive CD8 resident memory T cells.
What are the hallmark features of DiHS/DRESS and what immunological abnormalities are associated with it?
DiHS/DRESS is marked by maculopapular/morbilliform lesions, lymphadenopathy, and peripheral eosinophilia. Immunological abnormalities include reactivation of viruses (e.g., HHV-6, EBV) and breakdown of peripheral tolerance, leading to conditions like Hashimoto thyroiditis and SLE.
What genetic factors contribute to Atopic Dermatitis (AD) and how do they affect immune response?
Atopic Dermatitis (AD) is influenced by genetic factors such as loss of function mutations in FLG and single nucleotide polymorphisms (SNPs) in immune-related genes (e.g., IL2, IL6RA). These factors lead to an increased type 2 immune response characterized by elevated IgE levels.
Describe the relationship between Netherton Syndrome and Atopic Dermatitis. What are the key features?
Netherton Syndrome is characterized by eczematous dermatitis and is associated with a mutation in SPINK5, a cell surface protease inhibitor. This mutation leads to increased activity of serine protease, compromising the barrier function of the stratum corneum, and is linked to elevated IgE levels in AD patients.
What is the significance of Staphylococcal dysbiosis in Atopic Dermatitis?
Staphylococcal dysbiosis correlates with AD disease activity. It can be managed through interventions like bleach baths and topical steroids, which can reverse microbial dysbiosis without antibacterial treatment. This dysbiosis is associated with increased susceptibility to Staphylococcus aureus infections.
How do dupilumab and tofacitinib function in the treatment of Atopic Dermatitis?
Dupilumab is an IL-4 and IL-13 blocker that has shown effectiveness in AD during phase 3 trials. Tofacitinib, a JAK inhibitor, has demonstrated improvements in eczema area and severity index (EASI) during phase IIa trials, indicating its potential in managing AD symptoms.
What are the key characteristics of psoriasis related to keratinocyte behavior?
- Hyperproliferative epidermis
- Reduced basal keratinocyte transit times
- Abnormal keratinocyte differentiation
- Neutrophilic and lymphocytic inflammation
- Prominent capillary loops extending to the superficial dermis
What role do cytokines TNFα, IL23, and IL17 play in psoriasis?
- TNFα: Coproduced by dermal dendritic cells; augments the effect of IL17 on keratinocytes.
- IL23: Required for TH17 development; composed of p19 and p40.
- IL17: Promotes neutrophil predominant inflammation and modulates gene expression in keratinocytes.
What are the major phenotypes of alopecia areata?
- Patchy
- Universalis (entire scalp)
- Totalis (entire integument)
How does the immune response contribute to the pathophysiology of alopecia areata?
- Lymphocyte predominant inflammation with a predilection to ANAGEN hair bulbs.
- Loss of immune privilege leads to targeting of hair follicles by lymphocytes.
- CD8 T cells and IFNγ induce hair follicle dystrophy and premature entry to catagen.
What is the significance of IL15 in alopecia areata?
- IL15 is crucial for CD8 T cell induction.
How does the immune response contribute to the pathophysiology of alopecia areata?
- Lymphocyte predominant inflammation with a predilection to ANAGEN hair bulbs.
- Loss of immune privilege leads to targeting of hair follicles by lymphocytes.
- CD8 T cells and IFNγ induce hair follicle dystrophy and premature entry to catagen.
What is the significance of IL15 in alopecia areata?
- IL15 is crucial for CD8 T cell induction and persistence.
- Neutralization of IL15 leads to attenuation of alopecia areata.
What is the role of JAK inhibitors in the treatment of alopecia areata?
- Selective JAK1 inhibitors have shown activity against alopecia areata in studies.
- JAK3 inhibitors do not show significant responses according to phase II studies.
What is the mechanism of action of biologics targeting IL-17A in psoriasis?
IL-17A promotes neutrophil-predominant inflammation and modulates gene expression in keratinocytes. Anti-IL-17A biologics like Secukinumab block this pathway, reducing inflammation.
What cytokine is critical for the persistence of CD8+ T cells in alopecia areata?
IL-15 is critical for the induction and persistence of CD8+ T cells in alopecia areata.
What cytokines does Ustekinumab target in psoriasis treatment?
Ustekinumab targets the p40 subunit shared by IL-12 and IL-23, modulating both TH1 and TH17 pathways.
What is the rationale for using JAK inhibitors in alopecia areata?
JAK inhibitors target the JAK-STAT pathway, which is critical for the activity of CD8+ T cells, IFN-γ, and IL-15 in alopecia areata.
What is the role of IL-23 in psoriasis?
IL-23 is required for TH17 development and promotes the production of IL-17, which drives neutrophilic inflammation.
What immune cells are involved in the loss of immune privilege in hair follicles in alopecia areata?
CD8+ cytotoxic T cells and IFN-γ induce hair follicle dystrophy and premature entry into the catagen phase.
What is the mechanism of action of methotrexate in psoriasis treatment?
Methotrexate is an antimetabolite that modulates keratinocyte growth and gene expression, reducing inflammation.
What is the target of Infliximab in psoriasis treatment?
Infliximab targets TNF-α, reducing inflammation in psoriasis.
What cytokine does Guselkumab target in psoriasis treatment?
Guselkumab targets the p19 subunit of IL-23, reducing TH17-mediated inflammation.
What is the role of HLA-DR alleles in alopecia areata?
HLA-DR alleles encode MHC class II antigens, which are involved in presenting antigens to CD4+ T cells, promoting disease progression.
What is the significance of SNPs in the MHC class I locus in psoriasis?
SNPs in the MHC class I locus confer the largest genetic risk for psoriasis.
What are the key immunological factors involved in the pathophysiology of psoriasis?
- TH1 mediated: Psoriasis is primarily driven by TH1 cells.
- IFNγ: An important effector cytokine in psoriasis.
- TNFα, IL23, IL17: Elevated in psoriasis lesions.
- TH17: Produces IL17, promoting neutrophil inflammation.
- IL17: Modulates gene expression in keratinocytes.
- TNFα: Coproduced by dermal dendritic cells, augments IL17 effects.
- IL23: Required for TH17 development, composed of p19 and p40.
How does the loss of immune privilege contribute to the pathogenesis of alopecia areata?
- Loss of immune privilege: Normal hair follicles (HFs) lose their immune privilege, making them susceptible to lymphocyte attack.
- Lymphocyte predominant inflammation: Predilection for ANAGEN hair bulbs leads to hair loss.
- CD8 T cells and IFNγ: Induce hair follicle dystrophy and premature entry into catagen phase.
- IL15: Critical for CD8 T cell induction and persistence; neutralization leads to attenuation of alopecia areata.
What are the major phenotypes of alopecia areata and their associations with autoimmune diseases?
Phenotype | Description | Association with Autoimmune Diseases |
|—————–|———————————-|—————————————|
| Patchy | Localized patches of hair loss | May be associated with thyroiditis |
| Universalis | Total scalp hair loss | Associated with other autoimmune diseases |
| Totalis | Hair loss over entire integument | Associated with other autoimmune diseases |
What is the significance of JAK inhibitors in the treatment of alopecia areata?
- JAK inhibitors: Selective JAK1 inhibitors show activity against alopecia areata in studies.
- CD8 T cells, IFNγ, IL15: Their involvement suggests a critical role for JAK and STAT pathways in disease progression.
- JAK3 inhibitors: Do not show significant efficacy in alopecia areata treatment.
- Clinical responses: Significant responses to JAK inhibitors have been observed in phase II studies.
What is the major autoantigen in pemphigus vulgaris?
The major autoantigen in pemphigus vulgaris is Dsg3, which mediates cell adhesion between keratinocytes in the lower layers of the epidermis.
How does pemphigus foliaceus differ from pemphigus vulgaris?
Pemphigus foliaceus primarily affects the skin and is associated with the major autoantigen Dsg1, while pemphigus vulgaris involves Dsg3 and affects both the skin and mucous membranes.
What are the clinical features of bullous pemphigoid?
Bullous pemphigoid is characterized by urticarial lesions, subsequent tense bullae, and erosions on mucosa. The major autoantigen is Collagen XVII (COL17).
What is the significance of IgE in some patients with bullous pemphigoid?
In some patients with bullous pemphigoid, the presence of IgE may indicate an allergic component or heightened immune response, contributing to the disease’s pathology.
What is the role of Rituximab in the treatment of pemphigus?
Rituximab binds to the cell surface protein CD20 expressed by B cells, leading to the depletion of normal and autoreactive B cells.
How do chimeric autoantigen receptor (CAAR) T cells function in the treatment of pemphigus?
CAAR T cells are genetically modified T cells that express Dsg3. When these CAAR T cells bind to B cells expressing surface anti-Dsg3 IgG, they become activated and subsequently destroy Dsg3-reactive B cells.
What autoimmune condition is likely in a pregnant woman with tense bullae and urticarial lesions?
The condition is likely pemphigoid gestationis, and the primary autoantigen is collagen XVII (COL17/BP180).
What is the primary autoantigen targeted in pemphigus vulgaris?
The primary autoantigen is desmoglein 3 (Dsg3), which mediates cell adhesion in the lower layers of the epidermis.
What is the primary autoantigen in pemphigus foliaceus?
The primary autoantigen is desmoglein 1 (Dsg1), which is expressed by superficial epidermal keratinocytes.
What immune mechanism is involved in bullous pemphigoid with C3 deposition?
Local complement activation attracts neutrophils, which produce metalloproteinases, contributing to tissue damage.
What underlying condition is often associated with paraneoplastic pemphigus?
Paraneoplastic pemphigus is often associated with an underlying malignancy, such as lymphoma or thymoma.
What is the primary target in IgA pemphigus?
The primary target is desmocollin 1, a desmosomal component.
What is the likely immunological link between pemphigoid gestationis and autoimmune thyroiditis?
Both conditions involve autoantibodies, with pemphigoid gestationis targeting collagen XVII and thyroiditis involving thyroid-specific antigens.
What is the primary autoantigen in epidermolysis bullosa acquisita?
The primary autoantigen is type VII collagen (COL7).
What is the mechanism of action of Rituximab in pemphigus treatment?
Rituximab binds to CD20 on B cells, depleting both normal and autoreactive B cells.
What is the significance of IgE autoantibodies in bullous pemphigoid?
IgE autoantibodies may contribute to the inflammatory response in bullous pemphigoid.
What might the development of anti-Dsg1 autoantibodies indicate in pemphigus vulgaris?
The development of anti-Dsg1 autoantibodies may indicate progression to skin involvement in addition to mucosal lesions.
What is the immunological explanation for the increased incidence of thymoma in pemphigus foliaceus?
Thymoma leads to impaired central tolerance, increasing the risk of autoantibody production against Dsg1.
What role does Dsg3 play in pemphigus vulgaris?
Dsg3 mediates cell adhesion between keratinocytes in the lower layers of the epidermis. Autoantibodies against Dsg3 lead to flaccid bullae and erosions.
How does Pemphigus foliaceus differ from Pemphigus vulgaris in terms of affected areas?
Pemphigus foliaceus primarily affects the skin, while Pemphigus vulgaris affects both the skin and mucous membranes.
What is the autoantibody profile of Bullous pemphigoid?
Bullous pemphigoid autoantibodies are primarily IgG against hemidesmosome components, particularly Collagen XVII (COL17).
What is the significance of Rituximab in pemphigus treatment?
Rituximab is considered safe and effective when combined with short-term corticosteroids.
Describe the mechanism of action of Chimeric autoantigen receptor (CAAR) T cells.
CAAR T cells bind to B cells expressing anti-Dsg3 IgG, activating and destroying Dsg3-reactive B cells.
