13 - Basic Principles of Immunologic Diseases in Skin (Pathophysiology of Immunologic/Inflammatory Skin Diseases) Flashcards
Typically low-molecular-weight chemicals and metals, which interact with endogeneous proteins to form immunogenic (complete) antigens
Haptens
Y/N: Evidence suggesting that genetic susceptibility to ACD is important is strong
No - not strong
Initial exposures to haptens that commonly elicit ACD inpatients signal via 2 major pathways involved in innate immunity
Inflammasomes and/or
Toll-like receptors
Phases of acute contact dermatitis/contact hypersensitivity
- Sensitization
- Elicitation
- Resolution
Cytokine, toll-like receptor and inflammasome-mediated activation of APCs
No skin inflammation
Sensitization
Cytokine, toll-like receptor and inflammasome-mediated activation of APCs
Skin inflammation elicited by T cells
Elicitation
Resident memory T cells poised for subsequent exposure
Resolution
Y/N: Because haptens easily penetrate epidermis and reach the dermis, both Langerhans cells and dermal dendritic cells encounter contact allergens
Yes
CD8alpha+ (DCs and DDCs/LCs), but not (DCs and DDCs/LCs), contribute to CD8+ T-cell responses during antiviral responses
DCs and DDCs
LCs
_____ T cells appear to be the primary mediators of skin inflammation in ACD, but _____ T-cell activation may be required for optimal _____ T-cell responses
CD8+
CD4+
CD8+
_____ T cells mediate rapid cutaneous hypersensitivity responses, whereas _____ T cells cause delayed responses
Resident memory
Central memory
_____ T cells are thought to play major roles in attenuation or termination of inflammation in cutaneous hypersensitivity
Regulatory
Severe cutaneous adverse reactions include
SJS
TEN
DiHS/DRESS
Commonly included as SCAR, but is, in general, less severe than SJS/TEN and DiHS/DRESS
AGEP
In cohorts of Han-Chinese patients, SJS/TEN that is caused by allopurinol and carbamazepine is strongly associated with the HLA haplotypes _____ and _____, respectively
B*58:01
B*15:02
Dapsone hypersensitivity syndrome, a form of DiHS/DRESS has been associated with the _____ haplotype in Asians
HLA-B*13:01
_____ T cells can be readily detected in SJS/TEN lesions, suggesting that these cells are pathogenic
Cytotoxic
Probably reflects the existence of clones of drug-reactive CD8+ resident memory T (TRM) cells that reman at sites of previous skin lesions where they are poised to respond if offending drugs are readministered
Fixed drug eruptions
Y/N: Cytotoxic responses are more prominent in DiHS/DRESS
No - less prominent
Hallmark feature of DiHS/DRESS
Peripheral eosinophila
Expansion of regulatory T cells may result in immunocompromise in the initial stage of DiHS/DRESS, allowing reactivation of _____ infections
Herpes virus
EB virus-specific CD8+ T cells are reported to be increased in the circulation and cause tissue damage in EB virus-infected tissues, including _____, that is typical of DiHS/DRESS
Liver
B cells, which serve as a reservoir for EB virus, also may be targeted because patients with DiHS/DRESS frequently experience
Hypogammaglobulinemia
_____ patients exhibit immunologic abnormalities long after resolution of the acute phase and may develop autoimmune diseases such as Hashimoto thyroiditis, SLE, and type I DM
DiHS/DRESS
Accentuated immune responses against herpes viruses and the occurrence of autoimmune diseases suggest that breakdown of peripheral tolerance is a major contributor to
DiHS/DRESS
Posits that drugs bypass classic antigen-processing mechanisms and trigger immune responses through direct, noncovalent interactions with human leukocyte antigen alleles and/or T-cell receptors that are expressed on cell surfaces
Pharmacologic interaction with immune receptors (p-i) concept
Could explain why drug reactions occur within hours to few days in patients after initial exposure to causative drugs
Pharmacologic interaction with immune receptors (p-i) concept
Proposes that drugs bind directly to T-cell receptors and promote inappropriate T-cell reactivity to self-antigens
Altered TCR repertoire model
Serum levels of IgE and CCL17 (TARC), both of which are characteristic of type 2 immune responses, are increased in
Atopic dermatitis
Atopic dermatitis patients harbor loss-of-function mutations in the gene encoding the structural protein
Filaggrin
Netherton syndrome, a disease with eczematous dermatitis as a prominent feature, is caused by mutations in the cell surface protease inhibitor
SPINK5
(Presence/Loss) of SPINK5 leads to increased activity of cell surface serine proteases that compromises the barrier function of the stratum corneum
Loss
Y/N: SPINK 5 polymorphisms have been associated not with AD, but with elevated IgE levels in patients with AD
Yes
Characterized by dermatitis and impaired Th17 responses leading to increased susceptibility to Th17 responses leading to increased susceptibility to Staphylococcus aureus colonization or infections
Caused by loss of function mutations in STAT3
Job syndrome (hyperIgE syndrome)
Commonly colonizes AD skin
S. aureus
Although _____% of non-AD patients carry S. aureus as a commensal microbe, both the abundance and relative frequency of S. aureus representation in the skin microbiome is increased in AD patients, even when their disease is quiescent
20-30
When patients experience acute exacerbation of AD, _____ become predominant in the skin microbiome
Staphylococci (primarily S. aureus)
Cutaneous application of S. aureus in AD caused eczema, whereas commensal _____ species did not
Corynebacterium
Humanized monoclonal anti-IgE antibody which effectively treats asthma, food allergies, and urticaria, but is not effective in AD
Omalizumab
Blocks IL-4 and IL-13 signaling by binding to IL-4Ralpha
Effective in AD
Dupilumab
Inhibit both JAK1 and JAK3
Have activity in inflammatory diseases including rheumatoid arthritis, psoriasis and alopecia areata
Tofacitinib
Ruxolitinib
The calcineurin inhibitor _____ is a remarkably effective antipsoriatic agent
Ability to modulate keratinocyte growth and gene expression
Cyclosporine
Lymphocyte-depleting agent: IL-2 receptor-directed cytotoxin
Denileukin diftitox
Lymphocyte-depleting agent: CD2-binding LFA-3/Fc fusion protein
Alefacept
Y/N: Denileukin diftitox and alefacept were too toxic to be routinely administered to psoriatic patients because they have broad-spectrum antilypmhocyte effects
Yes
Anti-TNFalpha neutralizing antibody (one of the first widely used biologics)
Infliximab
TNFalpha is coproduced by dermal dendritic cells that also produce _____, a cytokine that is required for Th-17 cell development
IL-23
IL-23 is a heterodimeric protein composed of IL-23-specific p19 as well as p40, a polypeptide that is shared with the Th1-promoting cytokine
IL-12
Anti-humn p40
Ustekinumab
Anti-IL-7A monoclonal antibodies
Secukinumab
Ixekinumab
Anti-IL-23 p19 monoclonal antibody
Guselkumab
Single nucleotide polymorphisms in the _____ locus confer the largest amount of genetic risk in both European and Chinese psoriasis populations
MHC Class I
Y/N: The accepted importance of Th17 cells in psoriasis would predict that variants of interest would occur in the MHC Class II locus, rather than the MHC Class I locus
Yes
Scalp biopsies obtained from the (center/periphery) of expanding alopecia areata lesions feature lymphocyte-predominant inflammation
Periphery
Preferential association of lesional lymphocytes with anagen hair _____, rather than the stem cell-containing bulge regions, is consistent with the characterization of AA as a nonscarring alopecia
Bulbs
Inflammatory lesions in AA is thought to result from loss of “_____” that is a property of normal hair follicles
May depend on low-level expression of MHC Class I and Class II antigens by HF keratinocytes and local production of immunosuppressive cytokines and perhaps neuropeptides
Immune privilege
_____ inhibitors can reverse hair loss by suppressing inflammation and by directly acting on hair follicles to induce hair growth
JAK
The cytokine _____ is known to be important for CD8+ T-cell induction and/or persistence, so it is not surprising that neutralization of _____ also attenuates AA activity
IL-15
Coadministration of CD4+ CD25- (helper) T cells with CD8+ (promotes/prevents) disease progression whereas coadministration of CD4+ CD25+ (regulatory) T cells with CD8+ T cells (promotes/prevents) disease induction
Promotes
Prevents
Most common autoimmune blistering disorders
Pemphigus
Pemphigoid
Desmoglein _____ is expressed in oral and esophageal mucosae
3
Two major antigens targeted in BP
Collagen XVII/BPAG1/BP230
BPAG2/BP180
Expressed on cell surfaces
Considered to be the major BP autoantigen
COL17
Y/N: The pathophysiologic role of anti-BP230 antibodies in BP is uncertain because BP230 is an intracellular protein
Yes
Caused by anti-COL7 antibodies
Epidermolysis bullosa acquisita
In BP patients, the majority of anti-COL17 IgG autoantibodies target the _____ domain
NC16a
_____ deposition in the basement membrane zone is universal in BP
C3
The increased incidence of pemphigus (especially PF) in patients with _____ suggests that impairment of central tolerance relates to the onset of pemphigus
Thymoma
Binds the cell surface protein CD20 that is expressed by B cells
Leads to depletion of both normal and autoreactive B cells in patients
Rituximab
