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Introduction to the Immune System¶

Chapter 360 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 360

Key Clinical Points¶

The human immune system possesses three core properties: a highly diverse repertoire of antigen receptors, immune memory, and immunologic tolerance.
Adaptive immunity is based on specific antigen recognition by clonotypic receptors (T and B cells) resulting from gene rearrangement during development.
Innate immunity utilizes germline-encoded Pattern Recognition Receptors (PRRs) to detect Pathogen-Associated Molecular Patterns (PAMPs).
Toll-like receptors (TLRs) are critical PRRs that activate signaling pathways (MyD88, TRIF) leading to cytokine production.
Autoinflammatory diseases result from mutations in innate inflammatory controls, specifically the inflammasome.
Autoimmune diseases involve overreactive adaptive immune cells (T and B cells) producing pathogenic responses.
Crystallopathies (e.g., gout) are caused by crystal deposits that trigger the inflammasome.
T-cell exhaustion occurs in chronic infections (HIV-1, HCV) and malignancies where persistent antigen exposure impairs memory function.
Genetic variants in nucleic acid-sensing receptors (TLR7, TLR9, MyD88) can drive autoimmunity or autoinflammatory disease.
The complement system provides a rapid innate response via the classical, lectin, and alternative pathways.

DEFINITION & OVERVIEW¶

• Immune System Overview: Evolutionarily developed to protect the host from microbes and their virulence factors. • Core Properties: → Diversity: Highly diverse repertoire of antigen receptors for nearly infinite pathogens. → Memory: Ability to mount rapid recall immune responses. → Tolerance: Mechanism to avoid damage to self-tissues. • Adaptive Immune System:

Definition (Harrison's 22e): "Recently evolved system of immune responses mediated by T and B lymphocytes. Immune responses by these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and just as well throughout the life of the organism. Additional cells of the adaptive immune system include various types of antigen-presenting cells (APCs)." • B Lymphocytes: Bone marrow-derived; express surface immunoglobulin (BCR); secrete specific antibodies. • B Regulatory Cells: Suppressive B cells; inhibit inflammation via cytokines like IL-10. • T Lymphocytes: Thymus-derived; mediate adaptive cellular responses (helper, regulatory, cytotoxic). • T-cell Exhaustion: State where persistent antigen disrupts memory function; common in malignancies and chronic infections (HIV-1, HCV). • T Follicular Helper T cells (TFH): CD4 T cells; regulated by bcl-6; produce IL-4 and IL-21; drive B-cell differentiation/affinity maturation. • T-cell Subsets: ◦ T1: CD4 helper; T-bet regulated; produces IFN-γ, IL-2, and TNF-β; cell-mediated immunity. ◦ T2: CD4 helper; STAT6 and GATA3 regulated; produces IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13; regulates antibody/eosinophil responses. ◦ T9: CD4; PU.1 regulated; secretes IL-9; involved in atopic disease and IBD. ◦ T13: TFH; GATA3 regulated; produces IL-4, IL-5, and IL-13. ◦ T17: CD4; RORγt regulated; secretes IL-17, IL-22, and IL-26; involved in autoimmune/inflammatory disorders. • Innate Immune System: Definition (Harrison's 22e): "Ancient immune recognition system of host cells bearing germline-encoded pattern recognition receptors (PRRs) that recognize pathogens and trigger a variety of mechanisms of pathogen elimination." • Innate Lymphoid Cells (ILCs): Lymphocytes without diversified antigen receptors; include ILC1, ILC2, and ILC3. • Natural Killer (NK) Cells: Type of ILC; kill cells with low/no HLA class I; mirror CD8 cytotoxic T cells. • NK T Cells: Innate-like lymphocytes; invariant TCR-α chain; coexpress NK receptors; recognize lipid antigens. • Tolerance: Nonresponsiveness to antigens (central in thymus/bone marrow or peripheral via deletion/anergy). • Autoinflammatory Diseases: Hereditary disorders; recurring severe inflammation/fever due to mutations in innate inflammatory controls (inflammasome). • Autoimmune Diseases: Disorders where adaptive immune cells (T and B) become overreactive, producing pathogenic responses. • Crystallopathies: Tissue crystal deposits (e.g., monosodium urate) that activate the inflammasome; e.g., gout.

Immune Cell Markers (Table 360-1)¶

• Key CD Markers: ◦ CD1a, CD1c, CD1d: Present lipid antigens to TCRgammadelta T cells or NK T cells. ◦ CD2: T/NK; involved in activation, anergy, and cytokine production. ◦ CD3: Associates with the TCR; ζ is the signal transduction component. ◦ CD4: T-cell selection/activation; primary receptor for HIV-1. ◦ CD8: T-cell selection/activation; signal transduction with p56lck. ◦ CD14: TLR4 mediates with LPS and other PAMP activation of innate immunity. ◦ CD16a (FcγRIIIa): Mediates phagocytosis and ADCC. ◦ CD19, CD20: B-cell development, activation, and differentiation. ◦ CD21: Associated with CD19/CD81; Epstein-Barr virus receptor. ◦ CD22: Cell adhesion; signaling through association with p72sky, p53/56lyn, PI3 kinase, SHP1, fLCγ. ◦ CD23: Regulates IgE synthesis, cytokine release by monocytes. ◦ CD28: Co-stimulatory for T-cell activation; determines activation vs. anergy. ◦ CD40: B-cell activation, proliferation, and differentiation; formation of GCs; isotype switching; rescue from apoptosis. ◦ CD45 (LCA): Present on all leukocytes; involved in T/B activation and signaling. ◦ CD64 (FcγRI): Mediates phagocytosis and ADCC. ◦ CD80, CD86: Co-regulators of T-cell activation; signal via CD28 or inhibit via CD152 (CTLA-4). ◦ CD95 (Fas): Mediates apoptosis. ◦ CD134 (OX40): T-cell survival, cytokine stimulation. ◦ CD137 (4-1BB): T-cell co-stimulation. ◦ CD152 (CTLA-4): Inhibits T-cell proliferation. ◦ CD154 (CD40L): Co-stimulatory for T-cell activation, B-cell proliferation and differentiation. ◦ CD274 (PD-1): Inhibits T-cell proliferation. ◦ CD278 (ICOS): T-cell activation. ◦ CD357 (GTTR): T-cell activation. ◦ CD223 (LAG-3): T-cell inhibition. ◦ CD226 (DNAM-1): T-cell activation. ◦ CD252 (OX40L): T-cell survival, cytokine stimulation. ◦ CD272 (BTLA): T-cell inhibition. ◦ CD112: T-cell activation (DNAM-1), T-cell inhibition (TIGIT). ◦ CD155: T-cell inhibition (TIGIT, CD96), T-cell activation (DNAM-1). ◦ CD137: T-cell co-stimulation. ◦ CD274: Inhibits TCR activation. ◦ CD278: T-cell activation. ◦ CD357: T-cell activation. ◦ CD152: Inhibits T-cell proliferation. ◦ CD154: Co-stimulatory for T-cell activation, B-cell proliferation and differentiation. ◦ CD279 (PD-1): Inhibits T-cell proliferation.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Innate Immunity Mechanisms: ◦ Recognition of PAMPs (highly conserved microbial structures) by germline-encoded PRRs. ◦ Key components: TLRs, C-type lectin receptors (CLRs), RLRs, and NOD-like receptors (NLRs). ◦ Complement System: Cascading enzymes/proteins; functions include opsonization, anaphylatoxin production, and direct lysis. ◦ Autophagy: Lysosomal degradation to control intracellular pathogens (e.g., mycobacteria) and enhance MHC II presentation. • Pattern Recognition Receptors (PRRs): ◦ TLRs: Transmembrane proteins; 11 types in humans; activate signaling for T/B cell recruitment. ◦ NLRs & RLRs: Intracellular sensors; scan cytoplasm for pathogens; form inflammasomes. ◦ Inflammasome: Large cytoplasmic complexes (e.g., NLRP, NLRC4); link sensing of PAMPs to activation of IL-1β and IL-18. • Toll-like Receptor (TLR) Signaling Pathways (Flowchart 1): 1. TLR4 Pathway A (Non-canonical): TLR4 → TRAM/TRIF → IRF3 → IFN-β production. 2. TLR4 Pathway B (Canonical): TLR4 → MyD88 → IRAK → TRAF-6 → MAPK / NF-κB → Inflammatory cytokines/chemokines. 3. TLR2/1 or 2/6 Complex: TLR2 → MyD88 → IRAK → TRAF-6 → MAPK / NF-κB → Inflammatory cytokines/chemokines. 4. TLR3 Pathway: TLR3 → TRIF → IRF3 → IFN-β production. 5. TLR5, 7, 8, and 9 Pathways: TLR5/7/8/9 → MyD88 → IRAK → TRAF-6 → MAPK / NF-κB → Inflammatory cytokines/chemokines. • NK Cell Activation Logic (Flowchart 2): 1. No HLA class I AND No activating ligands → No response. 2. HLA class I present AND No activating ligands → No response (Inhibitory signal dominates). 3. No HLA class I AND Activating ligands present → NK attacks target cells (Missing self). 4. HLA class I present AND Activating ligands present → Outcome determined by balance of signals. • Clinical Significance of TLRs: ◦ TLR4 mutations can protect from LPS-induced shock or asthma. ◦ Inflammasome mutations lead to autoinflammatory syndromes (e.g., FMF, CAPS). ◦ Crystallopathies: Crystal deposits (monosodium urate) activate inflammasomes → inflammation/tissue damage.

PRRs and Ligands (Table 360-3)¶

• TLR Summary: ◦ TLR1, 2, 6: Sense lipopeptides (Bacteria, viruses). ◦ TLR3: Sense dsRNA (Virus) via TRIF. ◦ TLR4: Sense LPS (Bacteria, virus) via MyD88/TRIF. ◦ TLR5: Sense Flagellin (Bacteria). ◦ TLR7, 8, 9: Sense ssRNA/CpG-DNA (Virus, bacteria, protozoa). ◦ TLR11: Sense Profilin-like molecules (Protozoa).

Genetic Variants and Disease (Table 360-4)¶

• DNASE1/L3: LOF → SLE. • TLR7: GOF → SLE. • MyD88: No known disease (GOF). • ADA2: LOF → DADA2. • TREX1: LOF → various (Chilblain lupus, etc.). • TMEM173 (STING): LOF → STING-associated vasculopathy. • SAMHD1: LOF → Chilblain lupus?" • RNASEH2A/B/C: LOF → AGS 4, 2, 3. • IFIH1 (MDA5): GOF → AGS 7. • RIGI (DDX58): GOF → Singleton-Merten syndrome 2.

Inflammasome Mutations (Table 360-5)¶

• NLRP1: Autoinflammation with arthritis/dyskeratosis; CAPS. • NLRC4: AIFEC, FMF. • Clinical Correlation: Polymorphisms in inflammasomes can protect against or increase risk of infections (e.g., HCV, M. leprae) and autoimmune diseases (e.g., Addison, Celiac).

CLINICAL FEATURES¶

• Innate Cell Roles (Table 360-6): ◦ Macrophages: Phagocytosis; produce IL-1, TNF-α, IL-12; activate T1 responses. ◦ Dendritic Cells (DCs): Interstitial DCs (IL-12/IL-10); Langerhans DCs (IL-12) → potent activators of T and B cells. ◦ ILC2: Mediate response to parasites; produce IL-4, IL-5, IL-13; recruit CD4 T2 cells. ◦ NK-T Cells: Recognize lipid antigens; produce IL-4; recruit T2 responses. ◦ Eosinophils: Kill parasites; produce IL-5 → Ig-specific antibody response. ◦ Epithelial Cells: Produce antimicrobial peptides; produce TGF-β → IgA-specific response. • Cytokine Profiles (Table 360-7): ◦ IFN-α: Antiviral, antitumor; stimulates T/Macrophage/NK activity. ◦ IFN-γ: Regulates Macrophage/NK activation; promotes T1 differentiation. ◦ TNF-β: Cell cytotoxicity; lymph node/spleen development. ◦ G-CSF: Regulates myelopoiesis; enhances neutrophil survival. Clinical use in reversing neutropenia after cytotoxic chemotherapy. ◦ IL-32: Angiogenesis, pro-inflammatory. • Chemokine Signaling (Table 360-8): ◦ CCR1: Linked to Rheumatoid arthritis, MS. ◦ CCR3: Linked to Allergic asthma/rhinitis. ◦ CCR5: HIV-1 co-receptor; transplant rejection. ◦ CCR7: T and DC migration to lymph nodes. ◦ CCR9: Homing of T cells/IgA+ plasma cells to intestine (IBD). ◦ CXCR3-A: Linked to inflammatory skin disease, MS. ◦ CXCR4: HIV-1 co-receptor; tumor metastasis. ◦ XCR1: Rheumatoid arthritis, IgA nephropathy.

DIAGNOSTIC APPROACH¶

Pathogen Recognition: Identification of PAMPs by PRRs (TLR, NLR, RLR) or activation of the Complement system.
Signal Transduction: Activation of intracellular pathways (e.g., MyD88/TRIF) leading to transcription factor activation (NF-κB, IRF3).
Effector Recruitment: Release of cytokines and chemokines to recruit specific T and B cell subsets (T1, T2, T9, T13, T17).
Adaptive Response: Differentiation into memory cells for long-term protection.
Migration Logic: Multi-step adhesion cascade involving Selectins (rolling), Integrins (adhesion/activation), and Chemokines (homing to lymph nodes via CCR7).

MANAGEMENT & TREATMENT¶

Targeting Innate Pathways: Potential for modulating TLR signaling or inflammasome activation in autoinflammatory diseases.
Complement Management: Clinical management of deficiencies (e.g., C3, C5-C9) to prevent pyogenic infections or immune-complex diseases.
Therapeutic Agents: ◦ IFN-α: Used therapeutically in viral and autoimmune conditions. ◦ G-CSF: Used for reversing neutropenia after cytotoxic chemotherapy.
Vaccine Development: Utilizing TLR pathways to enhance vaccine efficacy.

PROGNOSIS & COMPLICATIONS¶

• Complement Deficiencies: ◦ C3, C5-C9: Risk of recurrent Neisseria infections and immune-complex diseases. ◦ C1q, C4, C2: Associated with immune-complex syndromes and pyogenic infections. • T-cell Exhaustion: Result of persistent antigen in malignancies and chronic viral infections (HIV-1, HCV). ◦ Leads to impaired memory function and reduced ability to clear infection.

SPECIAL CONSIDERATIONS¶

• Crystallopathies: Gout (monosodium urate) as a trigger for inflammasome activation. • T-cell Exhaustion: Hallmark of chronic infection (HIV, HCV) and malignancy. • Immune Tolerance: Critical to prevent autoimmunity; failure leads to tissue damage.

KEY PEARLS & CLINICAL TRAPS¶

• Immune System Core: Diversity, Memory, Tolerance. • Innate vs. Adaptive: Innate (Ancient, PRRs, fast) vs. Adaptive (Recent, TCR/BCR, specific). • TLR Signaling: TLR4 is a major hub for both MyD88 and TRIF pathways; TLR3 is unique to TRIF. • Inflammasome: Key link between innate sensing and IL-1β/IL-18 production; mutations cause autoinflammatory disease. • Complement: Essential for opsonization, anaphylatoxin release, and direct lysis. • Cytokine/Chemokine Roles: Specific chemokines (e.g., CCR7, CCR9) drive specific cell homing to tissues like lymph nodes or the gut.

Reference Tables¶

TABLE 360-1 Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens¶

Harrison's 22e, p.2757

SURFACE ANTIGEN (OTHER NAMES)	FAMILY	MOLECULAR MASS, kDa	DISTRIBUTION	LIGAND(S)	FUNCTION
CD1a (T6, HTA-1)	Ig	49	CD, cortical thymocytes, Langerhans type of DCs	TCRγδ T cells, NK T cells	CD1 molecules present lipid antigens of intracellular bacteria such as Mycobacterium leprae and M. tuberculosis to TCRγδT cells or NK T cells
	Ig	45	CD, cortical thymocytes, Langerhans type of DCs	TCRγδ T cells, NK T cells
CD1c	Ig	43	DC, cortical thymocytes, subset of B cells, Langerhans type of DCs	TCRγδ T cells, NK T cells
	Ig	37	Cortical thymocytes, intestinal epithelium, Langerhans type of DCs	TCRγδ T cells, NK T cells
CD2 (T12, LFA-2)	Ig	50	T, NK	CD58, CD48, CD59, CD15	Alternative T-cell activation, T-cell anergy, T-cell cytokine production, T- or NK-mediated cytolysis, T-cell apoptosis, cell adhesion
	Ig	γ:25–28, δ:21– 28, ε:20–25, η:21–22, ζ:16	T, NK T	Associates with the TCR
CD4 (T4, Leu-3)	Ig	55	T, myeloid	MHC-II, HIV gp120, IL-16, SABP	T-cell selection, T-cell activation, signal transduction with p56lck, primary receptor for HIV-1
	Ig	40	T, NK	K-12 (CD7L)
CD8 (T8, Leu-2)	Ig	34	T, subset of NK	MHC-I	T-cell selection, T-cell activation, signal transduction with p56lck
	LRG	53–55	M, G (weak), not by myeloid progenitors	Endotoxin (lipopolysaccharide), lipoteichoic acid, PI
CD16a (FcγRIIIa)	Ig	50–80	NK, macrophages, neutrophils	Fc portion of IgG	Mediates phagocytosis and ADCC
	Ig	95	B (except plasma cells), FDC	Not known
CD20 (B1)	Unassigned	33–37	B (except plasma cells)	Not known	Cell signaling, may be important for B-cell activation and proliferation
	RCA	145	Mature B, FDC, subset of thymocytes	C3d, C3dg, iC3b, CD23, EBV
CD22 (BL-CAM)	Ig	130–140	Mature B	CDw75	Cell adhesion, signaling through association with p72sky, p53/56lyn, PI3 kinase, SHP1, fLCγ
	C-type lectin	45	B, M, FDC	IgE, CD21, CD11b, CD11c
CD28	Ig	44	T, plasma cells	CD80, CD86	Co-stimulatory for T-cell activation; involved in the decision between T-cell activation and anergy
	Ig	40	NK, macrophages, neutrophils	Fc portion of IgG
CD40	TNFR	48–50	B, DC, EC, thymic epithelium, MP, cancers	CD154 (CD40L)	B-cell activation, proliferation, and differentiation; formation of GCs; isotype switching; rescue from apoptosis
	PTP	180, 200, 210, 220	All leukocytes	Galectin-1, CD2, CD3, CD4
CD45RA	PTP	210, 220	Subset T, medullary thymocytes, “naive” T	Galectin-1, CD2, CD3, CD4	Isoforms of CD45 containing exon 4 (A), restricted to a subset of T cells
	PTP	200, 210, 220	All leukocytes	Galectin-1, CD2, CD3, CD4
CD45RC	PTP	210, 220	Subset T, medullary thymocytes, “naive” T	Galectin-1, CD2, CD3, CD4	Isoforms of CD45 containing exon 6 (C), restricted to a subset of T cells
	PTP	180	Subset T, cortical thymocytes, “memory” T	Galectin-1, CD2, CD3, CD4
CD64 (FcγRI)	Ig	45–55	Macrophages and monocytes	Fc portion of IgG	Mediates phagocytosis and ADCC
	Ig	60	Activated B and T, MP, DC	CD28, CD152 (CTLA-4)
CD86 (B7-2, B70)	Ig	80	Subset B, DC, EC, activated T, thymic epithelium	CD28, CD152 (CTLA-4)	Co-regulator of T-cell activation; signaling through CD28 stimulates and through CD152 inhibits T-cell activation
	Ig	55–100	Neutrophils, eosinophils, monocytes, and MP	Fc portion of IgG

TABLE 360-2 Major Components of the Innate Immune System Pattern recognition Toll-like receptors (TLRs), C-type lectin…¶

Harrison's 22e, p.2758

Pattern recognition receptors (PRRs)	Toll-like receptors (TLRs), C-type lectin receptors (CLRs), retinoic acid–inducible gene (RIG)-1-like receptors (RLRs), and NOD-like receptors (NLRs)
Cells	Macrophages, dendritic cells, innate lymphoid cells (ILC1, ILC2, ILC3, NK cells, lymphoid tissue inducer [LTi] cells), mucosal-associated invariant T (MAIT) cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells

TABLE 360-3 Pattern Recognition Receptors (PRRs) and Their Ligands¶

Harrison's 22e, p.2759

PRR	LOCALIZATION	LIGAND	ORIGIN OF THE LIGAND
TLR
TLR1	Plasma membrane	Triacyl lipoprotein	Bacteria
TLR2	Plasma membrane	Lipoprotein	Bacteria, viruses, parasite, self
TLR3	Endolysosome	dsRNA	Virus
TLR4	Plasma membrane	LPS	Bacteria, viruses, self
TLR5	Plasma membrane	Flagellin	Bacteria
TLR6	Plasma membrane	Diacyl lipoprotein	Bacteria, viruses
TLR7 (human TLR8)	Endolysosome	ssRNA	Virus, bacteria, self
TLR9	Endolysosome	CpG-DNA	Virus, bacteria, protozoa, self
TLR10	Endolysosome	Unknown	Unknown
TLR11	Plasma membrane	Profilin-like molecule	Protozoa
	Cytoplasm Cytoplasm Cytoplasm	Short dsRNA, triphosphate dsRNA Long dsRNA Unknown
NLR
NOD1	Cytoplasm	iE-DAP	Bacteria
NOD2	Cytoplasm	MDP	Bacteria
	Plasma membrane Plasma membrane Plasma membrane	β2-Glucan β2-Glucan SAP130
MYD88
	TRIF			TRAM	MYD88			TIRAP				MYD88
													TLR9
		TRIF
					IRF3		IRAK CpG
											ssRNA
						TLR7 Endosome
										TRAF-6		or TLR8
TLR3
dsRNA									MAPK			NF-κB
Endosome NF-κB

Harrison's 22e, p.2760

GENE	PROTEIN	CHANGE IN FUNCTION	LOCATION	LIGAND OR PARTNER	AUTOIMMUNE OR AUTOINFLAMMATORY DISEASE IN OMIM	OMIM NUMBER	LUPUS SUSCEPTIBILITY ALLELES
DNASE1	DNASE1	LOF	Extracellular	dsDNA (NETs)	SLE	152700	Yes
	DNASE1L3	LOF	Extracellular	Nucleosomes exposed on microparticles or apoptotic bodies	SLE16	614420
TLR7	TLR7	GOF	Endosomal	ssRNA, 2’3’cGMP	SLE 17	301080	Yes
	TLR9	–	Endosomal	CpG dsDNA	N/A	–
MyD88	MyD88	–	Endosomal	TLRs	N/A (GOF)	–	No
	ADA2	LOF	Endolysosomal	Adenosine, 2’-deoxyadenosine	Sneddon syndrome Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (DADA2)	182410 615688
DNASE2	DNASE2	LOF	Lysosomal	Exogenous DNA	Autoinflammatory-pancytopenia syndrome	619858	No
	TREX1	LOF	Cytoplasmic	DNA (retroviral/retrotransposon)	AGS 1 Chilblain lupus Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations Susceptibility to SLE	225750 610448 192315 152700
TMEM173	STING	LOF	Cytoplasmic	cGAMP and excess DNA	STING-associated vasculopathy, infantile-onset	615934	Yes
	cGAS	–	Cytoplasmic	Cytosolic DNA	N/A (GOF)	–
SAMHD1	SAMHD1	LOF	Cytoplasmic	dNTPs	Chilblain lupus?	614415	Yes
					AGS 5	612952
	RNASEH2A	LOF	Cytoplasmic	RNA in RNA-DNA hybrids	AGS 4	610333
RNASEH2B	RNASEH2B	LOF	Cytoplasmic	RNA in RNA-DNA hybrids	AGS 2	610181	Yes
	RNASEH2C	LOF	Cytoplasmic	RNA in RNA-DNA hybrids	AGS 3	610329
IFIH1	MDA5	GOF	Cytoplasmic	Long dsRNA	AGS 7	615846	Yes
					Singleton-Merten syndrome 1	182250
RIGI	DDX58	GOF	Cytoplasmic	Short dsRNA	Singleton-Merten syndrome 2	616298	No
	MAVS	–	Cytoplasmic	–	N/A (GOF)	–
AIM2	AIM2	–	Cytoplasmic	Cytosolic dsDNA	N/A	–	No
	IFI16	–	Nuclear	Viral DNA or damaged self-DNA	N/A (GOF)	–

TABLE 360-5 Mutations in Innate Inflammasome Molecules Associated with Clinical Disease Inherited Inflammasomopathies¶

Harrison's 22e, p.2761

Inherited Inflammasomopathies
MUTATED GENE	DISEASE	INHERITED PATTERN AND EFFECT	PHENOTYPE	PREDOMINANT EFFECTOR CELLS
NLRP1	NLRP1-associated autoinflammation with arthritis and dyskeratosis	Autosomal dominant GoF	Hyperkeratotic ulcerative skin lesions, fever, arthritis, ANA	Keratinocytes
	Cryopyrin-associated periodic syndromes (CAPS)	Autosomal dominant GoF	Spectrum from cold-induced urticaria and fever to CNS inflammation and bone overgrowth
NLRC4	Autoinflammatory infantile fever with enterocolitis (AIFEC)	Autosomal dominant GoF	Recurrent MAS, enterocolitis, cold-induced fever and urticaria, CNS inflammation	Monocytes/macrophages
	Familial Mediterranean fever (FMF)	Autosomal recessive LoF or gene-dosage-dependent autosomal dominant GoF	Fever, serositis, rash, SAA amyloidosis
Genetic Polymorphisms in Inflammasome Components and Human Infectious Diseases
INFECTIOUS AGENT/DISEASE	GENE	VARIANT ID	EFFECT ON INFLAMMASOME ACTIVATION	ASSOCIATION
Candida albicans (recurrent vulvovaginal candidiasis)	NLRP3	rs74163773	Increased	Risk
	NLRP3	rs12065526	Unknown
HCV	NLRP3	rs1539019; rs35829419	Unknown; increased	Protection
	NLRP3 IFI16	rs10754558 rs1417806	Increased Increased
HPV	NLRP1	rs11651270	Increased	Protection
	NLRP3	rs10754558	Increased	Protection
	IFI16	rs2276404	Increased
HTLV	NLRP3	rs10754558	Increased	Protection
	NLRC4	rs212704	Decreased
Mycobacterium leprae	NLRP1	rs2670660, rs12150220	Increased	Protection
		rs2137722	(Haplotype)
	NLRP3 CARD8 NLRC4	rs10754558 rs10754558 rs6509365 rs385076	Increased Increased Unknown Decreased
Plasmodium vivax	NLRP1	rs12150220	Increased	Risk
	NLRP3	rs4612666	Increased
Streptococcus pneumoniae	NLRP1	rs11651270	Increased	Risk
	CARD8	rs2043211	Increased
	NLRP1 CASP1	rs11691270 rs501192	Increased Unknown
Genetic Polymorphisms in Inflammasome Components and Autoimmune in Polygenic Autoinflammatory Diseases
Addison disease	NLRP1	rs12150220	Increased	Risk
	NLRP3 MEFV CARD8	rs4612666 rs224204 rs2043211	Increased Unknown Increased
Autoimmune thyroiditis	NLRP1	rs12150220, rs2670660	Increased	Risk
	AIM2	rs855873	Unknown	Risk
	AIM2 IFI16	rs855873 rs6940	Unknown Decreased
Celiac disease	NLRP3	rs35829419	Increased	Protection; risk
	NLRP3	rs35829419 rs10754558 rs10925019 rs4925648 rs4353135, rs55646866; rs4266924, rs6672995, rs10733113	Increased Increased Increased Unknown Unknown Decreased; unknown

TABLE 360-6 Cells of the Innate Immune System and Their Major Roles in Triggering Adaptive Immunity¶

Harrison's 22e, p.2763

CELL TYPE	MAJOR ROLE IN INNATE IMMUNITY	MAJOR ROLE IN ADAPTIVE IMMUNITY
Macrophages	Phagocytose and kill bacteria; produce antimicrobial peptides; bind LPS; produce inflammatory cytokines	Produce IL-1 and TNF-α to upregulate lymphocyte adhesion molecules and chemokines to attract antigen-specific lymphocyte. Produce IL-12 to recruit T1 T helper cell responses; upregulate co-stimulatory H and MHC molecules to facilitate T and B lymphocyte recognition and activation. Macrophages and dendritic cells, after LPS signaling, upregulate co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86) that are required for activation of pathogen-specific T cells. There are also Toll-like proteins on B cells and dendritic cells that, after LPS ligation, induce CD80 and CD86 on these cells for T-cell antigen presentation.
	Produce large amounts of interferon-α (IFN-α), which has antitumor and antiviral activity, and are found in T-cell zones of lymphoid organs; they circulate in blood
Myeloid DCs are of two types: interstitial and Langerhans-derived	Interstitial DCs are strong producers of IL-12 and IL-10 and are located in T-cell zones of lymphoid organs, circulate in blood, and are present in the interstices of the lung, heart, and kidney; Langerhans DCs are strong producers of IL-12; are located in T-cell zones of lymph nodes, skin epithelia, and the thymic medulla; and circulate in blood	Interstitial DCs are potent activators of macrophage and mature DCs to phagocytose invading pathogens and present pathogen antigens to T and B cells.
	Weakly cytotoxic, dependent on T-bet transcription factor, first line of defense against viruses and bacteria
ILC2 cells	Mediate innate responses to parasites/helminths, repair damaged tissues by producing amphiregulin	Produce IL-4, IL-5, IL-13; recruit CD4 T2 T cells H
	Innate immune response to extracellular bacteria and gut microbiome
Lymphoid tissue inducer (LTi) cells	Critical for formation of secondary lymphoid tissue during embryogenesis	Produce lymphotoxin for lymph node and Peyer’s patch development in which adaptive immune responses occur
	Kill foreign and host cells that have low levels of MHC+ self- peptides. Express NK receptors that inhibit NK function in the presence of high expression of self-MHC.
NK-T cells	Lymphocytes with both T-cell and NK surface markers that recognize lipid antigens of intracellular bacteria such as Mycobacterium tuberculosis by CD1 molecules and kill host cells infected with intracellular bacteria	Produce IL-4 to recruit T2 helper T-cell responses, IgG1 and IgE H production
	Phagocytose and kill bacteria, produce antimicrobial peptides
Eosinophils	Kill invading parasites	Produce IL-5, which recruits Ig-specific antibody responses
	Release TNF-α, IL-6, and IFN-γ in response to a variety of bacterial PAMPs
Epithelial cells	Produce antimicrobial peptides; tissue-specific epithelia produce mediator of local innate immunity; e.g., lung epithelial cells produce surfactant proteins (proteins within the collectin family) that bind and promote clearance of lung-invading microbes	Produces TGF-β, which triggers IgA-specific antibody responses

TABLE 360-7 Cytokines and Cytokine Receptors CYTOKINE IL-25 (also called¶

Harrison's 22e, p.2766

CYTOKINE	RECEPTOR	CELL SOURCE	CELL TARGET	BIOLOGIC ACTIVITY
IL-25 (also called IL-17E)	IL-17RB	CD4 T cells, mast cells	Fibroblasts, endothelium, epithelium, macrophages	Proinflammatory; induces cytokine production
	IL-20R1/IL-10R2	T1, T17 T cells, synovial cells H H	Epithelial cells
IL-27	gp130t wsx-1	Myeloid cells such as macrophages and DCs	T cells	Collaborates with other cytokines to activate T-cell differentiation
	IFN-λ receptor 1, IL-28Rα, IL-10Rβ	Myeloid lineage cells; epithelial cells	Epithelial cells
IL-28B (IFN-λ3)	IFN-λ receptor 1, IL-28Rα, IL-10Rβ	Myeloid lineage cells; epithelial cells	Epithelial cells	Enhanced clearance of viral infections
	IFN-λ receptor 1, IL-28Rα, IL-10Rβ	Myeloid lineage cells; epithelial cells	Epithelial cells
IL-30 (p28 of IL-27)	IL-27Rα; gp130+wsx-1	Activated macrophages and DCs; epithelial malignancies	Monocytes	Anti-inflammatory cytokines; upregulation of breast and prostate cancer metastasis
	IL-31RA/ oncostatin MRβ	Eosinophils, CD4 T cells	Epithelial cells, monocytes
IL-32 (NK4)	?	Monocytes, T cells, NK cells, epithelial cells	Monocytes, macrophages, bone marrow stroma	Angiogenesis, IL-2 production in bone marrow, proinflammatory
	ST-2	Endothelial cells, epithelial cells, fibroblasts, mucosal epithelium	T cells, mast cells eosinophils, basophils, ILC2s
IL-34 (C16of77)	CSF-1R, PTP-E, CD138	Neurons, Treg, myeloid cells		Anti-inflammatory myeloid cell proliferation
	IL-12Rβ2/ IL-12Rβ2, gp130/ gp130, IL-12Rb2/ gp130	Tregs, Bregs	Macrophages, T cells
IL-36α IL36β IL36γ IL36RA (IL-1 F5)	IL-36R	Keratocytes Mucosal epithelial cells Monocytes-macrophages Langerhans cells CD4 T cells	Epithelial cells, macrophages, DCs, T cells, B cells, plasma cells	T responses, proinflammatory H
	IL-1R, IL-36R, IL-1RA PL1	Epithelial cells, B cells	Epithelial cells, macrophages, DCs, T cells, B cells, plasma cells
IL-39	?	Macrophages, DCs, B cells	Neutrophils	Proinflammatory
	?	B cells, bone marrow/stroma	B cells
IFN-α	Type I interferon receptor	All cells	All cells	Promotes antiviral activity; stimulates T-cell, macrophage, and NK-cell activity; direct antitumor effects; upregulates MHC class I antigen expression; used therapeutically in viral and autoimmune conditions
	Type I interferon receptor	All cells	All cells
IFN-γ	Type II interferon receptor	T cells, NK cells	All cells	Regulates macrophage and NK-cell activations; stimulates immunoglobulin secretion by B cells; induction of class II histocompatibility antigens; T1 H T-cell differentiation
	TNFrI, TNFrII	Monocytes-macrophages, mast cells, basophils, eosinophils, NK cells, B cells, T cells, keratinocytes, fibroblasts, thymic epithelial cells	All cells except erythrocytes
TNF-β	TNFrI, TNFrII	T cells, B cells	All cells except erythrocytes	Cell cytotoxicity, lymph node and spleen development
	LTβR	T cells	All cells except erythrocytes
G-CSF	G-CSFr; gp130	Monocytes-macrophages, fibroblasts, endothelial cells, thymic epithelial cells, stromal cells	Myeloid cells, endothelial cells	Regulates myelopoiesis; enhances survival and function of neutrophils; clinical use in reversing neutropenia after cytotoxic chemotherapy
	GM-CSFr, common β	T cells, monocytes-macrophages, fibroblasts, endothelial cells, thymic epithelial cells	Monocytes-macrophages, neutrophils, eosinophils, fibroblasts, endothelial cells

TABLE 360-8 CC, CXC 1 , CX 3 , C 1 , and XC Families of Chemokines and Chemokine Receptors¶

Harrison's 22e, p.2769

CHEMOKINE RECEPTOR	CHEMOKINE LIGANDS	CELL TYPES	DISEASE CONNECTION
CCR1	CCL3 (MIP-1α), CCL5 (RANTES), CCL7 (MCP-3), CCL14 (HCC1)	T cells, monocytes, eosinophils, basophils	Rheumatoid arthritis, multiple sclerosis
	CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3), CCL13 (MCP-4), CCL16 (HCC4)	Monocytes, dendritic cells (immature), memory T cells
CCR3	CCL11 (eotaxin), CCL13 (eotaxin-2), CCL7 (MCP-3), CCL5 (RANTES), CCL8 (MCP-2), CCL13 (MCP-4)	Eosinophils, basophils, mast cells, T2, H platelets	Allergic asthma and rhinitis
	CCL17 (TARC), CCL22 (MDC)	T cells (T2), dendritic cells (mature), H basophils, macrophages, platelets
CCR5	CCL3 (MIP-1α), CCL4 (MIP-1α), CCL5 (RANTES), CCL11 (eotaxin), CCL14 (HCC1), CCL16 (HCC4)	T cells, monocytes	HIV-1 co-receptor (T cell–tropic strains), transplant rejection
	CCL20 (MIP-3α, LARC)	T cells (T regulatory and memory), B cells, dendritic cells
CCR7	CCL19 (ELC), CCL21 (SLC)	T cells, dendritic cells (mature)	Transport of T cells and dendritic cells to lymph nodes, antigen presentation, and cellular immunity
	CCL1 (1309)	T cells (T2), monocytes, dendritic cells H
CCR9	CCL25 (TECK)	T cells, IgA+ plasma cells	Homing of T cells and IgA+ plasma cells to the intestine, inflammatory bowel disease
	CCL27 (CTACK), CCL28 (MEC)	T cells
CXCR1	CXCL8 (interleukin-8), CXCL6 (GCP2)	Neutrophils, monocytes	Inflammatory lung disease, COPD
	CXCL8, CXCL1 (GROα), CXCL2 (GROα), CXCL3 (GROα), CXCL5 (ENA-78), CXCL6	Neutrophils, monocytes, microvascular endothelial cells
CXCR3-A	CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC)	Type 1 helper cells, mast cells, mesangial cells	Inflammatory skin disease, multiple sclerosis, transplant rejection
	CXCL4 (PF4), CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC)	Microvascular endothelial cells, neoplastic cells
CXCR4	CXCL12 (SDF-1)	Widely expressed	HIV-1 co-receptor (T cell–tropic), tumor metastases, hematopoiesis
	CXCL13 (BCA-1)	B cells, follicular helper T cells
CXCR6	CXCL16 (SR-PSOX)	CD8+ T cells, natural killer cells, and memory CD4+ T cells	Inflammatory liver disease, atherosclerosis (CXCL16)
	CX3CL1 (fractalkine)	Macrophages, endothelial cells, smooth-muscle cells
XCR1	XCL1 (lymphotactin), XCL2	T cells, natural killer cells	Rheumatoid arthritis, IgA nephropathy, tumor response

TABLE 360-9 NK-Cell Receptors, Cognate Ligands, and Their Known Signaling Domains/Proximal Adapters RECEPTOR Inhibitory¶

Harrison's 22e, p.2772

RECEPTOR	GENE	LIGAND	SIGNALING DOMAINS AND PROXIMAL ADAPTERS
Inhibitory KIR		Conserved epitopes on HLA I (“KIR ligands”)	ITIM, Src phosphatases
KIR2DL1	KIR2DL1	HLA-C2 alleles (Lys80)
KIR2DL2	KIR2DL2	HLA-C1 alleles (Asp80); HLA-C2 alleles (Lys80)
KIR2DL3	KIR2DL3	HLA-C1 alleles (Asp80)
KIR3DL1	KIR3DL1	HLA-B alleles carrying the Bw4 motif; HLA-A alleles carrying the Bw4 motif
KIR3DL2	KIR3DL2	HLA-A03, HLA-A11 carrying specific peptides
KIR2DL4	KIR2DL4	HLA-G
KIR2DL5		CD155
		HLA-C2, HLA-C1, HLA-F, certain configurations of HLA- peptide combinations
	KIR2DS1	HLA-C2 alleles (Lys80) carrying specific peptides
	KIR2DS2	HLA-C1 (Asp80) HLA-A*11
	KIR2DS3	Unknown
		HLA-F
		Unknown
Natural cytotoxicity receptors (NCRs)
NKp30	NCR3	B7-H6, BAT-3, heparan sulfates
NKp44	NCR2	PDGF, heparan sulfates, PCNA
NKp46	NCR1	Viral hemagglutinins, heparan sulfates, vimentin, ecto-calreticulin
SLAMF1	SLAMF1
CD48	SLAMF4, CD2
LY9	SLAMF3
CD244	SLAMF2
SLAMF6	SLAMF6
SLAMF7	SLAMF7
SLAMF8	Unknown

TABLE 360-10 Association of KIRS with Disease DISEASE Psoriatic arthritis Spondylarthritides¶