Uncontrolled activation of macrophages with a marked increase in circulating cytokines. _Clinical characteristics:_ High fever, HSmegaly, high ferritin and TG, low fibrinogen, and NK cells. Hemophagocytosis in BM biopsy. Dx Criteria (5 of 8): 1) fever, 2) splenomegaly, 3) cytopenia (≥2 lines), 4) hyperTG or hypofibrinogenemia, 5) hemophagocytosis, 6) hepatitis, 7) Low or absent NK cell activity, 8) ferritin \>500, and soluble CD25 (sI-2 recptor) \>2,400.

Cells Involved in Immune Response Flashcards by Santiago Alvarez

NKT Cells

These are not NK cells

Limited T cell receptor repertoire Vα24/Jα18 and Vβ11

CD1-restricted

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Monocyte

Express IgG, IgA, IgE
Monoblast → (GM-CSF, IL-6) → Monocyte
CD14 (a component of TLR4 and an LPS receptor)
Mature ⇒ CD16 (produce TNFαandIL-12)
Chemokines (attract monocytes to the lungs): CCL2, CCL3, CCL4, CCL5.

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Macrophage

Express: CD14, CD16, CD11b/CD18 (Mac-1), CD33, and CD36
Develop in response → GM-CSF
Classical M1 (LPS and/or Th1 → INFγ) ⇒ secrete TNFα, IL6, IL-1β → Activate T cells
Alternative M2 (steroids and/or Th2 → IL-4, IL-13, IL-10)
TNFα promotes granuloma formation

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HLH

Uncontrolled activation of macrophages with a marked increase in circulating cytokines.

Clinical characteristics: High fever, HSmegaly, high ferritin and TG, low fibrinogen, and NK cells.
Hemophagocytosis in BM biopsy.
Dx Criteria (5 of 8): 1) fever, 2) splenomegaly, 3) cytopenia (≥2 lines), 4) hyperTG or hypofibrinogenemia, 5) hemophagocytosis, 6) hepatitis, 7) Low or absent NK cell activity, 8) ferritin >500, and soluble CD25 (sI-2 recptor) >2,400.

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Dendritic Cells

Key fact: pDC lack CD11c, express CD123
Develop: GM-CSF and IL-4
Most important APCs (critical in starting germinal centers reactions)
Express B7-1/B7-2 (CD80/CD86) interacts with CD28 (costimultion/2nd signal)
DCs interact with epithelial cells (especially Der p1 and Th2 polarization)

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Langerhans Cell Histiocytosis

Rare malignancy of Langerhans cells
Eczema and/or seborrhea
1/2 cases: Limited to lytic bone lesions. Other 1/2: Multisystem involvement.
Dx: Bipsy to confirm LC (CD1a, CD207)

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Mast Cell

Essential receptor: CD117 (KIT); essential cytokine: SCF; transcription factor: GATA2
Life-span: weeks-months
Surface receptors: FCεRI, FCεRII, FCεRIIa, FcγRI, C5aR, C3aR, Leukotriene receptors; ch__emokine: CCR3, CCR5, CXCR2, CXCR4; c__omplement: C5aR, C3a; PG: PGE2R; LT: CysLT1R, CysLT2R.
Preformed mediators (<15 min): Histamine, proteases, carboxypeptidase A, proteoglycans, TNFα; lipid-derived mediators (~10 - 30 min): PGD2, LTB4, LTC4, LTD4, LTE4; chemokines: IL-3,4, 5, 6, 8, 13, GM-CSF, TNFα, MIP-1α (CCL-3), RANTES (CCL-5)

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Basophil

Essential receptor: CD123 (IL-3R); essential cytokine: IL-3; transcription factor: GATA2
Life-span: Days
Surface receptors: FCεRI, FCεRIIb, CRTH2 (PGD2 receptor); chemokine: CCR2, CCR3; complement: CD11b, CD11c, CD35, CD88; PG: CRTH2 (PGD2 receptor)
Preformed mediators (<15 min): Histamine; lipid-derived mediators (~10 - 30 min): LTC4, LTD4, LTE4; chemokines: IL-3, 4, 5, 13, GM-CSF, TNFα, MIP-1α (CCL-3)

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Eosinophils (life-span: days-week)

Essential receptor: IL-5R, CCR3
Essential cytokine: IL-5, IL-3, GM-CSF
Transcription factor: GATA1
Surface receptors: FcγRII, FcαRI, CCR3, CRTH2 (PGD2 receptor), leukotriene receptors; chemokine: CCR1, CCR3; complement: CR1/CD25, CR3, CD88; PG: PGD2 type 2 receptor; LT: CysLT1R, CysLT2R
Preformed mediators (<15 min):
- Primary granules: CLC
- Secondary granules: MBP, eosinophilic cationic protein, eosinophil peroxidase, the eosinophil-derived neurotoxin, lysosomal hydrolase, lysophospholipase
Lipid-derived mediators (~10 - 30 min): PGE2, LTC4, LTD4, LTE4
Cytokines/chemokines: IL-3, 4, 5, 8, 10, 12, 13, 16, 18, TGFβ, TNFα , CCL-5, CCL-11

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Arachidonic Acid Pathway

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Mast Cell Activation and Signaling

IgE Receptor/FcεR:

Tetrameric: one α chain (binding site for IgE), one β chain (four transmembrane domains and one ITAM), two γ chains (covalently linked, each one contains one ITAM; main signaling component)
Trimeric: one α chain and two γ chains (DC, monocytes, and eosinophils)

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Where does Derp-p-1 cleaves?

Low-affinity IgE receptor /FcεRII/CD23

C-type lectin found on mature B-cells, activated macrophages, eosinophils, dendritic cells, and platelets

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Primary immunodeficiencies with elevated IgE

Hyper IgE syndrome, Wiskott-Aldrich Syndrome, Omenn syndrome, IPEX, atypecal complete DGS

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Unlike mast cells, basophils do not produce:

Tryptase, chymase, carboxypeptidase, heparin, PGD2, and LTB4

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Charcot-Leyden Crystals

Eosinophils → Primary Granules

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Eosinophils Secondary Granules

MBP
Eosinophil cationic protein
Eosinophil peroxidase
Eosinophil-derived neurotoxin

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Infections most commonly responsible for CGD infection

S aureus
Aspergillus spp.
Chromobacterium violaceum
Pseudomonas cepacia
Nocardia spp.
Salmonella typhimurium
Serratia marcescens
Mycobacterium fortuitum
Klebsiella spp.
E coli
Actinomyces spp.
Legionella bosmanii
C difficile

Eosinophils migrate to tissue in response to:

RANTES (CCL-5)
Eotaxin (eotaxin-1, CCL-11, eotaxin-2, CCL-24)

Eosinophils release cytokines:

IL-1
IL-2
IL-4
IL-5
IL-6
IL-8
IL-13
TNF

Infections with high eosinophils (remember most bacterial/viral infections suppress eosinophils)

HIV (secondary to adrenal insufficiency, HIV medications, or HIV itself)
Parasitic infections, especially those that invade the tissue (Strongyloides)
Isospora belli and Sarcocystis, but not other protozoa
Chronic TB

Neutrophil

Attracted to tissue by IL-8 (CXCL-8)
- Also, INFγ, fMLP, MIP-1, LTB-4, C5a, and interactions between Sialy-Lewis X, E-/P-selectins, and LFA-1/ICAM-1
Express surface receptors for IgG and IgA
Survival/differentiation/proliferation: G-CSF, GM-CSF, and IL-3

Platelet

Formation regulated by thrombopoietin (secreted by liver and kidney)
Surface receptor: IgG and CD23
Activated: Exposed collagen and vWF
Thromboxane A2 → Activates more platelets
Release: ADP/ATP, calcium, serotonin, TGFβ, PF4, PDGF, vWF, and fibrinogen
Clump: vWF ⇔ GPIIb/IIIa

Drug-induced thrombocytopenia (autoantibody?)

Antibody against platelet antigen PF4

ITP (autoantibody?)

GP2b3a

TTP (autoantibody?)

**ADAMTS13**

Wiskott-Aldrich syndrome

Triad: Eczema, infections, thrombocytopenia (as well as small platelets) Defect: WASp used in cell signaling _Remember: Elevated IgE_

Receptor Rhinovirus

ICAM-1

Receptor Influenza

Glycans

Receptor Adenovirus

Integrins and CD80/86

Produce by epithelial cells

**TSLP, GM-CSF, IL-25, and IL-33**

**Suppression of β defensins and cathelicidins**

Atopic dermatitis, IL-4, and IL-13 expression

Bullous Skin Disorders

Pemphigus Vulgaris

Intercellular IgG and IgM to Desmoglein 3 (desmosome)

Pemphigus Foliaceous

Intercellular IgG to Desmoglein 1 (desmosome)

Bullous Pemphigoid

Linear IgG at basement membrane zone to BPAg1 (BP 230) and BPAg2 (BP 180) [hemidesmosome]

Pemphigoid gestationis (herpes gestationis)

Linear IgG at basement membrane zone to BPAg1 (BP 230) and BPAg2 (BP 180) [hemidesmosome]

Dermatitis Herpetiformis

Granular IgA in dermis to Transglutaminase (subepidermal)

Linear IgA dermatosis

Linear IgA in basement membrane zone to BPAg2 (BP 180) [hesmidesmosome]

**Adhesions Molecules Used for Transmigration of Leukocytes**

Anti-SMA (IgG autoantibody)

Type I autoimmune hepatitis