13: Basic Principles of Immunologic Diseases in Skin (Pathophysiology of Immunologic and Inflammatory Skin Diseases)

Question 1

What is the role of haptens in allergic contact dermatitis?

Answer 1

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.

Question 2

What are the two major pathways involved in innate immunity related to allergic contact dermatitis?

Answer 2

1. Inflammasomes: Activated by exposure to substances like urushiols and Cr2+, leading to the release of proinflammatory cytokines (IL1B, IL18, TNFa).
2. Toll-like receptors: Such as TLR4, which binds nickel and Cr2+, resulting in the production of IL1B, IL18, and IFN.

Question 3

What is the significance of CD8+ T cells in allergic contact dermatitis?

Answer 3

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).

Question 4

What are some severe cutaneous adverse reactions (SCARs) associated with drug reactions?

Answer 4

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.

Question 5

How does ethnicity influence genetic predisposition to drug reactions like SJS and TEN?

Answer 5

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.

Question 6

A patient presents with recurrent skin lesions after exposure to nickel. What molecular mechanisms are likely involved in this allergic contact dermatitis?

Answer 6

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.

Question 7

A patient develops severe skin blistering after taking allopurinol. What genetic predisposition might explain this reaction?

Answer 7

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.

Question 8

A patient with toxic epidermal necrolysis (TEN) is found to have HLA-B15:02. What drug might have triggered this reaction?

Answer 8

Carbamazepine is associated with TEN in patients with the HLA-B15:02 allele.

Question 9

What are the phases involved in allergic contact dermatitis and their significance?

Answer 9

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.

Question 10

How do Langerhans cells and dermal dendritic cells contribute to the immune response in allergic contact dermatitis?

Answer 10

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).

Question 11

What are the severe cutaneous adverse reactions (SCARs) associated with drug reactions, and what are their genetic predispositions?

Answer 11

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.

Question 12

What role do cytotoxic T cells play in SJS/TEN lesions?

Answer 12

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).

Question 13

What are the hallmark features of Drug-Induced Hypersensitivity Syndrome (DiHS) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)?

Answer 13

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.

Question 14

What genetic mutations are associated with Netherton Syndrome and its clinical features?

Answer 14

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.

Question 15

How does Job Syndrome affect immune response and what are its clinical implications?

Answer 15

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).

Question 16

What is the significance of Staphylococcal dysbiosis in Atopic Dermatitis?

Answer 16

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.

Question 17

What are the effects of Dupilumab and Tofacitinib in the treatment of Atopic Dermatitis?

Answer 17

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.

Question 18

A patient with atopic dermatitis shows elevated IgE levels. What genetic mutation might contribute to this condition?

Answer 18

A loss-of-function mutation in the FLG gene or SPINK5 polymorphisms could contribute to elevated IgE levels and compromised skin barrier function.

Question 19

A patient with drug-induced hypersensitivity syndrome (DiHS) shows peripheral eosinophilia and liver damage. What viral reactivation might be involved?

Answer 19

Reactivation of HHV-6, HHV-7, EBV, or CMV may be involved, with circulating EBV-specific CD8+ T cells potentially causing liver damage.

Question 20

A patient with atopic dermatitis is unresponsive to anti-IgE therapy. What alternative biologic might be effective?

Answer 20

Dupilumab, an IL-4 and IL-13 blocker, has shown efficacy in treating atopic dermatitis.

Question 21

A patient with fixed drug eruptions (FDEs) experiences recurrent lesions at the same site after drug re-exposure. What immune cells are responsible?

Answer 21

CD8+ resident memory T cells (TRMs) mediate the interface dermatitis seen in FDEs.

Question 22

A patient with Stevens-Johnson syndrome (SJS) shows CD8+ T cells along the dermoepidermal junction. What is the pathological mechanism?

Answer 22

CD8+ T cells mediate interface dermatitis and keratinocyte apoptosis, contributing to the lesions in SJS.

Question 23

A patient with Netherton syndrome has elevated IgE levels. What genetic mutation is responsible for this condition?

Answer 23

A mutation in the SPINK5 gene, which encodes a cell surface protease inhibitor, leads to increased serine protease activity and compromised skin barrier function.

Question 24

A patient with atopic dermatitis undergoes bleach baths. What is the therapeutic mechanism?

Answer 24

Bleach baths control atopic dermatitis by modifying the cutaneous microbiome and reducing Staphylococcal dysbiosis.

Question 25

A patient with drug-induced hypersensitivity syndrome (DiHS) develops autoimmune sequelae. What is the underlying immunological mechanism?

Answer 25

Breakdown of peripheral tolerance leads to immunological abnormalities, resulting in conditions like Hashimoto thyroiditis, SLE, or type 1 diabetes.

Question 26

A patient with atopic dermatitis shows increased CCL17 (TARC) levels. What immune response is this associated with?

Answer 26

Increased CCL17 levels are associated with a type 2 immune response.

Question 27

A patient with atopic dermatitis is treated with Tofacitinib. What is the expected outcome?

Answer 27

Tofacitinib, a JAK inhibitor, improves the eczema area and severity index (EASI) in atopic dermatitis.

Question 28

A patient with atopic dermatitis shows Staphylococcal dysbiosis. What treatment can reverse this without antibacterial therapy?

Answer 28

Topical steroids can reverse microbial dysbiosis in atopic dermatitis.

Question 29

A patient with atopic dermatitis is unresponsive to Omalizumab. Why might this be the case?

Answer 29

Omalizumab, an anti-IgE monoclonal antibody, is not effective in atopic dermatitis despite its efficacy in asthma and urticaria.

Question 30

What role do cytotoxic T cells play in SJS/TEN lesions and how do they differ in DiHS/DRESS?

Answer 30

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.

Question 31

How do Fixed Drug Eruptions (FDEs) manifest and what is their underlying mechanism?

Answer 31

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.

Question 32

What are the hallmark features of DiHS/DRESS and what immunological abnormalities are associated with it?

Answer 32

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.

Question 33

What genetic factors contribute to Atopic Dermatitis (AD) and how do they affect immune response?

Answer 33

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.

Question 34

Describe the relationship between Netherton Syndrome and Atopic Dermatitis. What are the key features?

Answer 34

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.

Question 35

What is the significance of Staphylococcal dysbiosis in Atopic Dermatitis?

Answer 35

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.

Question 36

How do dupilumab and tofacitinib function in the treatment of Atopic Dermatitis?

Answer 36

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.

Question 37

What are the key characteristics of psoriasis related to keratinocyte behavior?

Answer 37

- **Hyperproliferative epidermis** - **Reduced basal keratinocyte transit times** - **Abnormal keratinocyte differentiation** - **Neutrophilic and lymphocytic inflammation** - **Prominent capillary loops** extending to the superficial dermis

Question 38

What role do cytokines TNFα, IL23, and IL17 play in psoriasis?

Answer 38

- **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.

Question 39

What are the major phenotypes of alopecia areata?

Answer 39

1. **Patchy** 2. **Universalis** (entire scalp) 3. **Totalis** (entire integument)

Question 40

How does the immune response contribute to the pathophysiology of alopecia areata?

Answer 40

- **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.

Question 41

What is the significance of IL15 in alopecia areata?

Answer 41

- **IL15** is crucial for CD8 T cell induction.

Question 42

How does the immune response contribute to the pathophysiology of alopecia areata?

Answer 42

- 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.

Question 43

What is the significance of IL15 in alopecia areata?

Answer 43

- IL15 is crucial for CD8 T cell induction and persistence. - Neutralization of IL15 leads to attenuation of alopecia areata.

Question 44

What is the role of JAK inhibitors in the treatment of alopecia areata?

Answer 44

- Selective JAK1 inhibitors have shown activity against alopecia areata in studies. - JAK3 inhibitors do not show significant responses according to phase II studies.

Question 45

What is the mechanism of action of biologics targeting IL-17A in psoriasis?

Answer 45

IL-17A promotes neutrophil-predominant inflammation and modulates gene expression in keratinocytes. Anti-IL-17A biologics like Secukinumab block this pathway, reducing inflammation.

Question 46

What cytokine is critical for the persistence of CD8+ T cells in alopecia areata?

Answer 46

IL-15 is critical for the induction and persistence of CD8+ T cells in alopecia areata.

Question 47

What cytokines does Ustekinumab target in psoriasis treatment?

Answer 47

Ustekinumab targets the p40 subunit shared by IL-12 and IL-23, modulating both TH1 and TH17 pathways.

Question 48

What is the rationale for using JAK inhibitors in alopecia areata?

Answer 48

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.

Question 49

What is the role of IL-23 in psoriasis?

Answer 49

IL-23 is required for TH17 development and promotes the production of IL-17, which drives neutrophilic inflammation.

Question 50

What immune cells are involved in the loss of immune privilege in hair follicles in alopecia areata?

Answer 50

CD8+ cytotoxic T cells and IFN-γ induce hair follicle dystrophy and premature entry into the catagen phase.

Question 51

What is the mechanism of action of methotrexate in psoriasis treatment?

Answer 51

Methotrexate is an antimetabolite that modulates keratinocyte growth and gene expression, reducing inflammation.

Question 52

What is the target of Infliximab in psoriasis treatment?

Answer 52

Infliximab targets TNF-α, reducing inflammation in psoriasis.

Question 53

What cytokine does Guselkumab target in psoriasis treatment?

Answer 53

Guselkumab targets the p19 subunit of IL-23, reducing TH17-mediated inflammation.

Question 54

What is the role of HLA-DR alleles in alopecia areata?

Answer 54

HLA-DR alleles encode MHC class II antigens, which are involved in presenting antigens to CD4+ T cells, promoting disease progression.

Question 55

What is the significance of SNPs in the MHC class I locus in psoriasis?

Answer 55

SNPs in the MHC class I locus confer the largest genetic risk for psoriasis.

Question 56

What are the key immunological factors involved in the pathophysiology of psoriasis?

Answer 56

- 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.

Question 57

How does the loss of immune privilege contribute to the pathogenesis of alopecia areata?

Answer 57

- 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.

Question 58

What are the major phenotypes of alopecia areata and their associations with autoimmune diseases?

Answer 58

| 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 |

Question 59

What is the significance of JAK inhibitors in the treatment of alopecia areata?

Answer 59

- 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.

Question 60

What is the major autoantigen in pemphigus vulgaris?

Answer 60

The major autoantigen in pemphigus vulgaris is Dsg3, which mediates cell adhesion between keratinocytes in the lower layers of the epidermis.

Question 61

How does pemphigus foliaceus differ from pemphigus vulgaris?

Answer 61

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.

Question 62

What are the clinical features of bullous pemphigoid?

Answer 62

Bullous pemphigoid is characterized by urticarial lesions, subsequent tense bullae, and erosions on mucosa. The major autoantigen is Collagen XVII (COL17).

Question 63

What is the significance of IgE in some patients with bullous pemphigoid?

Answer 63

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.

Question 64

What is the role of Rituximab in the treatment of pemphigus?

Answer 64

Rituximab binds to the cell surface protein CD20 expressed by B cells, leading to the depletion of normal and autoreactive B cells.

Question 65

How do chimeric autoantigen receptor (CAAR) T cells function in the treatment of pemphigus?

Answer 65

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.

Question 66

What autoimmune condition is likely in a pregnant woman with tense bullae and urticarial lesions?

Answer 66

The condition is likely pemphigoid gestationis, and the primary autoantigen is collagen XVII (COL17/BP180).

Question 67

What is the primary autoantigen targeted in pemphigus vulgaris?

Answer 67

The primary autoantigen is desmoglein 3 (Dsg3), which mediates cell adhesion in the lower layers of the epidermis.

Question 68

What is the primary autoantigen in pemphigus foliaceus?

Answer 68

The primary autoantigen is desmoglein 1 (Dsg1), which is expressed by superficial epidermal keratinocytes.

Question 69

What immune mechanism is involved in bullous pemphigoid with C3 deposition?

Answer 69

Local complement activation attracts neutrophils, which produce metalloproteinases, contributing to tissue damage.

Question 70

What underlying condition is often associated with paraneoplastic pemphigus?

Answer 70

Paraneoplastic pemphigus is often associated with an underlying malignancy, such as lymphoma or thymoma.

Question 71

What is the primary target in IgA pemphigus?

Answer 71

The primary target is desmocollin 1, a desmosomal component.

Question 72

What is the likely immunological link between pemphigoid gestationis and autoimmune thyroiditis?

Answer 72

Both conditions involve autoantibodies, with pemphigoid gestationis targeting collagen XVII and thyroiditis involving thyroid-specific antigens.

Question 73

What is the primary autoantigen in epidermolysis bullosa acquisita?

Answer 73

The primary autoantigen is type VII collagen (COL7).

Question 74

What is the mechanism of action of Rituximab in pemphigus treatment?

Answer 74

Rituximab binds to CD20 on B cells, depleting both normal and autoreactive B cells.

Question 75

What is the significance of IgE autoantibodies in bullous pemphigoid?

Answer 75

IgE autoantibodies may contribute to the inflammatory response in bullous pemphigoid.

Question 76

What might the development of anti-Dsg1 autoantibodies indicate in pemphigus vulgaris?

Answer 76

The development of anti-Dsg1 autoantibodies may indicate progression to skin involvement in addition to mucosal lesions.

Question 77

What is the immunological explanation for the increased incidence of thymoma in pemphigus foliaceus?

Answer 77

Thymoma leads to impaired central tolerance, increasing the risk of autoantibody production against Dsg1.

Question 78

What role does Dsg3 play in pemphigus vulgaris?

Answer 78

Dsg3 mediates cell adhesion between keratinocytes in the lower layers of the epidermis. Autoantibodies against Dsg3 lead to flaccid bullae and erosions.

Question 79

How does Pemphigus foliaceus differ from Pemphigus vulgaris in terms of affected areas?

Answer 79

Pemphigus foliaceus primarily affects the skin, while Pemphigus vulgaris affects both the skin and mucous membranes.

Question 80

What is the autoantibody profile of Bullous pemphigoid?

Answer 80

Bullous pemphigoid autoantibodies are primarily IgG against hemidesmosome components, particularly Collagen XVII (COL17).

Question 81

What is the significance of Rituximab in pemphigus treatment?

Answer 81

Rituximab is considered safe and effective when combined with short-term corticosteroids.

Question 82

Describe the mechanism of action of Chimeric autoantigen receptor (CAAR) T cells.

Answer 82

CAAR T cells bind to B cells expressing anti-Dsg3 IgG, activating and destroying Dsg3-reactive B cells.