Introduction to the Immune System

2677CHAPTER 349

TABLE 349-4 Mutations in Innate Inflammasome Molecules Associated with Clinical Disease

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

NLRP3 Cryopyrin-associated periodic

syndromes (CAPS)

Autosomal dominant GoF Spectrum from cold-induced

urticaria and fever to CNS

inflammation and bone

overgrowth

Monocytes, granulocytes

(neutrophils), chondrocytes

NLRC4 Autoinflammatory infantile

fever with enterocolitis (AIFEC)

Autosomal dominant GoF Recurrent MAS, enterocolitis,

cold-induced fever and

urticaria, CNS inflammation

Monocytes/macrophages

MEFV Familial Mediterranean fever

(FMF)

Autosomal recessive LoF

or gene-dosage-dependent

autosomal dominant GoF

Fever, serositis, rash, SAA

amyloidosis

Neutrophils, monocytes,

serosal and synovial fibroblasts

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

Chlamydia trachomatis NLRP3 rs12065526 Unknown Risk

HCV NLRP3 rs1539019; rs35829419 Unknown; increased Protection

HIV-1 NLRP3 rs10754558 Increased Protection

IFI16 rs1417806 Increased Protection

HPV NLRP1 rs11651270 Increased Protection

NLRP3 rs10754558 Increased Protection

HSV-2 IFI16 rs2276404 Increased Protection

HTLV NLRP3 rs10754558 Increased Protection

Microbial infection in lungs NLRC4 rs212704 Decreased Risk

Mycobacterium leprae NLRP1 rs2670660, rs12150220 Increased Protection

rs2137722 (Haplotype)

Mycobacterium tuberculosis NLRP3 rs10754558 Increased Protection

rs10754558 Increased Risk

CARD8 rs6509365 Unknown Risk

NLRC4 rs385076 Decreased Protection

Plasmodium vivax NLRP1 rs12150220 Increased Risk

Renal parenchymal infections NLRP3 rs4612666 Increased Protection

Streptococcus pneumoniae NLRP1 rs11651270 Increased Risk

CARD8 rs2043211 Increased

Trypanosoma cruzi NLRP1 rs11691270 Increased Risk

CASP1 rs501192 Unknown Risk

Genetic Polymorphisms in Inflammasome Components and Autoimmune in Polygenic Autoinflammatory Diseases

Addison disease NLRP1 rs12150220 Increased Risk

Ankylosing spondylitis NLRP3 rs4612666 Increased Risk

MEFV rs224204 Unknown Risk

CARD8 rs2043211 Increased Protection

Autoimmune thyroiditis NLRP1 rs12150220, rs2670660 Increased Risk

AIM2 rs855873 Unknown Risk

Behçet disease AIM2 rs855873 Unknown Risk

IFI16 rs6940 Decreased

Celiac disease NLRP3 rs35829419 Increased Protection; risk

IBD: Crohn’s disease (CD) and

ulcerative colitis (UC) 

NLRP3 rs35829419 Increased Risk (men)

Increased Protection

rs10754558 Increased Risk

rs10925019 Unknown Risk

rs4925648 Unknown Risk

rs4353135, rs55646866;

rs4266924, rs6672995,

rs10733113

Decreased; unknown Risk

(Continued)

2678 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 349-4 Mutations in Innate Inflammasome Molecules Associated with Clinical Disease

INFECTIOUS AGENT/DISEASE GENE VARIANT ID

EFFECT ON INFLAMMASOME

ACTIVATION ASSOCIATION

IBD: Crohn’s disease (CD) and

ulcerative colitis (UC) (Cont.)

MEFV rs182674, rs224217, rs224225,

rs224224, rs224223, rs224222

Unknown Risk

CARD8 rs2043211 Increased Risk

Protection

rs1972619 Unknown Risk

HS purpura MEFV rs3743930 Unknown Risk

Kawasaki disease NLRP1 rs11651270, rs8079034,

rs3744717, rs11078571,

rs16954813, rs8079727

Increased (haplotype) Risk

Multiple sclerosis NLRP3 rs3806265, rs10754557 Unknown Risk

rs35829419 Increased Risk

NLRC4 rs479333 Decreased Protection

PFAPA CARD8 rs140826611 Unknown Risk

Psoriasis NLRP1 rs8079034 Unknown Risk

NLRP3 rs3806265, rs10754557 Unknown Risk

rs10733113 Unknown Risk

CARD8 rs2043211 Increased Risk

AIM2 rs2276405 Unknown Protection

Psoriatic JIA NLRP3 rs4353135 Decreased Risk

rs3806265 Unknown Risk

MEFV rs224204 Unknown Risk

Rheumatoid arthritis NLRP1 rs878329 Unknown Risk

NLRP3 rs35829419 Increased Risk

rs10754558 Increased Risk

rs10159239, rs4925648,

rs4925659

Unknown Risk

CASP5 rs9651713 Unknown Risk

SLE NLRP1 rs12150220, rs2670660 Increased Risk

Systemic sclerosis NLRP1 rs8182352 Unknown Risk

Type 1 diabetes NLRP1 rs12150220 Increased Risk

rs2670660, rs11651270 Increased Protection

NLRP3 rs10754558 Increased Protection

Vitiligo NLRP1 rs12150220 Increased Risk

rs2670660 Increased Risk

rs8182352 Unknown Risk

rs6502867 Unknown Risk

rs1008588 Unknown Risk

Note: Mutated gene and respective syndrome name are reported for inflammasomopathies, as well as inheritance pattern and effect of mutations, clinical phenotype, and

predominant disease effector cells. Inflammasome variants previously associated with infectious agents and/or diseases are briefly resumed from literature (https://www.

ncbi.nlm.nih.gov/pubmed). Significantly associated polymorphisms were grouped according to the infectious agent/disease. Infectious agent or disease (in alphabetical

order), gene name (gene), identification number of polymorphism (ID), resulting effect on inflammasome activation (“increased,” “decreased,” or “unknown”), cohort origin

(cohort) and eventually specifications (severity, etc.), sample size (n), and type (case/control or cases only), association result (“risk” or “protection”), and respective

reference are reported.

Abbreviations: ANA, antinuclear antibodies; CNS, central nervous system; GoF, gain-of-function; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human

papillomavirus; HS, Henoch-Schönlein; HSV, herpes simplex virus; HTLV, human T-lymphotropic virus; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; LoF,

loss-of-function; MAS, macrophage activation syndrome; PFAPA, periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis; SAA, serum amyloid A; SLE,

systemic lupus erythematosus.

Source: Reproduced with permission from FP Fernandes et al: Inflammasome genetics and complex diseases: A comprehensive review. Eur J Hum Genet 28:1307, 2020.

(Continued)

killing of target cells, which are usually malignant cell types, transplanted foreign cells, or virus-infected cells. Thus, NK cell cytotoxicity

may play an important role in immune surveillance and destruction of

malignant and virus-infected host cells. NK cell hyporesponsiveness is

also observed in patients with Chédiak-Higashi syndrome, an autosomal recessive disease associated with fusion of cytoplasmic granules

and defective degranulation of neutrophil lysosomes.

NK cells have a variety of surface receptors that have inhibitory

or activating functions and belong to two structural families. These

families include the immunoglobulin superfamily and the lectin-like

type II transmembrane proteins. NK immunoglobulin superfamily

receptors include the killer cell immunoglobulin-like activating or

inhibitory receptors (KIRs), many of which have been shown to have

HLA class I ligands. The KIRs are made up proteins with either two

(KIR2D) or three (KIR3D) extracellular immunoglobulin domains

(D). Moreover, their nomenclature designates their function as either

inhibitory KIRs with a long (L) cytoplasmic tail and immunoreceptor

tyrosine-based inhibitory motif (ITIM) (KIRDL) or activating KIRs

with a short (S) cytoplasmic tail (KIRDS). NK cell inactivation by KIRs

is a central mechanism to prevent damage to normal host cells. Genetic

studies have demonstrated the association of KIRs with viral infection

outcome and autoimmune disease (Table 349-8).

In addition to the KIRs, a second set of immunoglobulin superfamily receptors includes the natural cytotoxicity receptors (NCRs), which

Introduction to the Immune System

2679CHAPTER 349

include NKp46, NKp30, and NKp44. These receptors help to mediate

NK cell activation against target cells. The ligands to which NCRs bind

on target cells have been recently recognized to be comprised of molecules of pathogens such as influenza, cytomegalovirus, and malaria as

well as host molecules expressed on tumor cells.

NK cell signaling is, therefore, a highly coordinated series of inhibiting and activating signals that prevent NK cells from responding

to uninfected, nonmalignant self-cells; however, they are activated

to attack malignant and virally infected cells (Fig. 349-4). Recent

evidence suggests that NK cells, although not possessing rearranging

immune recognition genes, may be able to mediate recall for NK

cell responses to viruses and for immune responses such as contact

hypersensitivity.

Some NK cells express CD3 and invariant TCR-α chains and are

termed NK T cells. TCRs of NK T cells recognize lipid molecules

of intracellular bacteria when presented in the context of CD1

molecules on APCs. Upon activation, NK T cells secrete effector

cytokines such as IL-4 and IFN-γ. This mode of recognition of intracellular bacteria such as Listeria monocytogenes and Mycobacterium

tuberculosis by NK T cells leads to induction of activation of DCs and

is thought to be an important innate defense mechanism against these

organisms.

The receptors for the Fc portion of IgG (FcγRs) are present on NK

cells, B cells, macrophages, neutrophils, and mast cells and mediate

interactions of IgG with antibody-coated target cells, such as virally

infected cells. Antibody-NK interaction via antibody Fc and NK cell

FcR links the adaptive and innate immune systems and regulates the

mediation of IgG antibody effector functions such as ADCC. There are

both activation and inhibitory FcγRs. Activation FcRs, such as FcγRI

(CD64), FcγRIIa (CD32a), and FcγRIIIa (CD16a), are characterized

by the presence of an immunoreceptor tyrosine-based activating motif

(ITAM) sequence, whereas inhibitory FcRs, such as FcγRIIb (CD32b),

contain an ITIM sequence. There is evidence that dysregulation in

IgG-FcγR interactions plays roles in arthritis, multiple sclerosis, and

systemic lupus erythematosus.

Neutrophils, Eosinophils, and Basophils Granulocytes are

present in nearly all forms of inflammation and are amplifiers and

TABLE 349-5 Cells of the Innate Immune System and Their Major Roles in Triggering Adaptive Immunity

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 TH1 T helper cell responses; upregulate

co-stimulatory 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.

Plasmacytoid dendritic

cells (DCs) of lymphoid

lineage

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

IFN-α is a potent activator of macrophage and mature DCs to

phagocytose invading pathogens and present pathogen antigens to T

and B cells.

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.

ILC1 cells Weakly cytotoxic, dependent on T-bet transcription factor, first line

of defense against viruses and bacteria

Produce IFN-γ to recruit CD4 TH1 T cells

ILC2 cells Mediate innate responses to parasites/helminths, repair damaged

tissues by producing amphiregulin

Produce IL-4, IL-5, IL-13; recruit CD4 TH2 T cells

ILC3 cells Innate immune response to extracellular bacteria and gut

microbiome

Produce IL-22, IL-17, GM-CSF, lymphotoxin; recruit CD4 TH17 T cells

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

Natural killer (NK) cells Kill foreign and host cells that have low levels of MHC+ selfpeptides. Express NK receptors that inhibit NK function in the

presence of high expression of self-MHC.

Produce TNF-α and IFN-γ, which recruit TH1 helper T-cell responses

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 TH2 helper T-cell responses, IgG1 and IgE

production

Neutrophils Phagocytose and kill bacteria, produce antimicrobial peptides Produce nitric oxide synthase and nitric oxide, which inhibit apoptosis

in lymphocytes and can prolong adaptive immune responses

Eosinophils Kill invading parasites Produce IL-5, which recruits Ig-specific antibody responses

Mast cells and basophils Release TNF-α, IL-6, and IFN-γ in response to a variety of bacterial

PAMPs

Produce IL-4, which recruits TH2 helper T cell responses, and recruit

IgG1- and IgE-specific antibody responses

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

Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-4, IL-5, IL-6, IL-10, and IL-12, interleukin 4, 5, 6, 10, and 12, respectively; ILC, innate lymphoid

cell; MHC, major histocompatibility complex: LPS, lipopolysaccharide; PAMP, pathogen-associated molecular patterns; TGF, transforming growth factor; TH, helper T cell;

TNF-α, tumor necrosis factor-alpha.

Source: Adapted from R Medzhitov, CA Janeway: Curr Opinion Immunol 9:4, 1997. Copyright 1997.

2680 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Stem cell

Lymphoid precursor

T cell

CD4+

T cell

GATA3 G Bcl6 Tbet ATA3 RORγt PU 1 Fox3p

CD8+ cytotoxic

T cell

Kill pathogeninfected cells

Kill tumor cells

Plasmacytoid B cell

dendritic cell

Natural

killer cell

Monocyte/

macrophage

Dendritic

cell

IFN-α

antigen

presenting

Antibodydependent

cellular

cytotoxicity

tumor cell

killing

Antibodies

antigen

IL-12 antigen presentation

presentation

IL-1, IL-6

phagocytosis

of microbes

Neutrophilic,

eosinophilic,

or basophilic

granulocyte

IFN-α

antigen

presentation

TFH13

cell

TH1

cell

TH2

cell

TH17

cell

TH9

cell

T regulatory

cell

T follicular

helper cell (TFH)

IL-13 IFN-γ IL-4

IL-5

IL-13

IL-17

IL-22

IL-9 IL-10

TGF-β

IL-21

IgE

allergic

reaction

Antibody

responses;

stimulate

eosinophils

Linked to

autoimmune

disease

mediation

T-cell function

downregulation;

prevent autoimmune

disease

B-cell affinity

maturation

in germinal

centers

Cytotoxic

T-cell

responses

Differentiation/

activation

FIGURE 349-2 Model of immune effector cell development. Hematopoietic stem cells differentiate into T cells, antigen-presenting dendritic cells, natural killer cells,

macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, macrophages, and B cells, and peptide fragments of foreign antigen are presented

to CD4+ and/or CD8+ T cells. CD8+ T-cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T-cell generation, as well as induction of cytokine-producing

CD8+ cytotoxic T cells. Granulocytes (neutrophils, eosinophils, or basophils) are effector cells of the innate immune system and mediate anti-infectious agent activity

by cytokine production, infectious agent killing, or both. TH1 CD4+ T cells play an important role in defense against intracellular microbes and help in the generation of

CD8+ cytotoxic T cells. TH2 CD4+ T cells producing interferon (IFN) γ or interleukin (IL) 4, IL-5, or IL-13 regulate Ig class switching and determine the type of antibody produced.

TH17 cells secrete IL-17 and IL-22, TH9 cells secrete IL-9, and Tfh13 cells secrete IL-4, IL-5, and IL-13. TH17 and TH9 CD4 T cells are linked to mediation of autoimmune disease,

and Tfh13 cells are linked to IgE-mediated anaphylaxis. CD4+ T regulatory cells produce IL-10 and transforming growth factor (TGF)-β and downregulate T- and B-cell

responses once the microbe has been eliminated. Each of the types of CD4+ T cells are regulated by different transcription factors, and the key transcription factors are

shown in the circles above each CD4+ T-cell type.

Introduction to the Immune System

2681CHAPTER 349

TABLE 349-6 Cytokines and Cytokine Receptors

CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY

IL-1α, β Type I IL-1r, type II IL-1r Monocytes/macrophages,

B cells, fibroblasts, most

epithelial cells including thymic

epithelium, endothelial cells

All cells Upregulates adhesion molecule expression, neutrophil

and macrophage emigration, mimics shock, fever,

upregulates hepatic acute-phase protein production,

facilitates hematopoiesis

IL-2 IL-2r α, β, common γ T cells T cells, B cells, NK cells,

monocytes-macrophages

Promotes T-cell activation and proliferation, B-cell

growth, NK-cell proliferation and activation, enhanced

monocyte/macrophage cytolytic activity

IL-3 IL-3r, common β T cells, NK cells, mast cells Monocytes-macrophages, mast

cells, eosinophils, bone marrow

progenitors

Stimulates hematopoietic progenitors

IL-4 IL-4r α, common γ T cells, mast cells, basophils T cells, B cells, NK cells,

monocytes-macrophages,

neutrophils, eosinophils,

endothelial cells, fibroblasts

Stimulates TH2 helper T-cell differentiation and

proliferation; stimulates B-cell Ig class switch to

IgG1 and IgE anti-inflammatory action on T cells,

monocytes; produced by T follicular helper cells

in B-cell germinal centers that stimulate B-cell

maturation.

IL-5 IL-5r α, common γ T cells, mast cells, eosinophils Eosinophils, basophils, murine

B cells

Regulates eosinophil migration and activation

IL-6 IL-6r, gp130 Monocytes-macrophages,

B cells, fibroblasts, most

epithelium including thymic

epithelium, endothelial cells

T cells, B cells, epithelial

cells, hepatocytes,

monocytes-macrophages

Induces acute-phase protein production, T- and B-cell

differentiation and growth, myeloma cell growth, and

osteoclast growth and activation

IL-7 IL-7r α, common γ Bone marrow, thymic epithelial

cells

T cells, B cells, bone marrow

cells

Differentiates B-, T-, and NK-cell precursors, activates

T and NK cells

IL-8 CXCR1, CXCR2 Monocytes-macrophages, T

cells, neutrophils, fibroblasts,

endothelial cells, epithelial cells

Neutrophils, T cells,

monocytes-macrophages,

endothelial cells, basophils

Induces neutrophil, monocyte, and T-cell migration,

induces neutrophil adherence to endothelial cells

and histamine release from basophils, and stimulates

angiogenesis; suppresses proliferation of hepatic

precursors

IL-9 IL-9r α, common γ T cells Bone marrow progenitors, B

cells, T cells, mast cells

Induces mast cell proliferation and function,

synergizes with IL-4 in IgG and IgE production and

T-cell growth, activation, and differentiation

IL-10 IL-10r Monocytes-macrophages, T

cells, B cells, keratinocytes,

mast cells

Monocytes-macrophages, T

cells, B cells, NK cells, mast

cells

Inhibits macrophage proinflammatory cytokine

production, downregulates cytokine class II antigen

and B7-1 and B7-2 expression, inhibits differentiation

of TH1 helper T cells, inhibits NK cell function,

stimulates mast cell proliferation and function, B-cell

activation, and differentiation

IL-11 IL-11r α, gp130 Bone marrow stromal cells Megakaryocytes, B cells,

hepatocytes

Induces megakaryocyte colony formation and

maturation, enhances antibody responses, stimulates

acute-phase protein production

IL-12 (35-kDa

and 40-kDa

subunits)

IL-12r Activated macrophages,

dendritic cells, neutrophils

T cells, NK cells Induces TH1 T helper cell formation and lymphokineactivated killer cell formation; increases CD8+ CTL

cytolytic activity; ↓IL-17, ↑IFN-γ

IL-13 IL-13r/IL-4r α T cells (TH2) Monocytes-macrophages,

B cells, endothelial cells,

keratinocytes

Upregulates VCAM-1 and C-C chemokine

expression on endothelial cells and B-cell activation

and differentiation, and inhibits macrophage

proinflammatory cytokine production

IL-14 Unknown T cells Normal and malignant B cells Induces B-cell proliferation, inhibits antibody

secretion, and expands selected B-cell subgroups

IL-15 IL-15r α, common γ,

IL2r β

Monocytes-macrophages,

epithelial cells, fibroblasts

T cells, NK cells Promotes T-cell activation and proliferation,

angiogenesis, and NK cells

IL-16 CD4 Mast cells, eosinophils, CD8+ T

cells, respiratory epithelium

CD4+ T cells, monocytesmacrophages, eosinophils

Promotes chemoattraction of CD4+ T cells, monocytes,

and eosinophils; inhibits HIV-1 replication; inhibits

T-cell activation through CD3/T-cell receptor

IL-17 IL-17r CD4+ T cells Fibroblasts, endothelium,

epithelium, macrophages

Enhances cytokine/chemokine secretion; promotes

delayed-type reactions

IL-18 IL-18r (IL-1R-related

protein)

Keratinocytes, macrophages T cells, B cells, NK cells Upregulates IFN-γ production, enhances NK cell

cytotoxicity

IL-21 IL-δγ chain/IL-21R CD4 T cells NK cells Downregulates NK cell–activating molecules, NKG2D/

DAP10; produced by T follicular helper cells in B-cell

germinal centers that stimulate B-cell maturation.

IL-22 IL-22 R1/IL-10R2 DC, T cells Epithelial cells Innate responses against bacterial pathogens;

promotes hepatocyte survival

IL-23 IL-12Rb1/IL23R Macrophages, other cell types T cells Opposite effects of IL-12 (↑IL-17, ↑IFN-γ)

IL-24 IL-20R1/IL-20R2

IL-22R1/IL-20R2

Macrophages,

TH2 cells

Nonhematopoietic cells such

as fibroblasts

Promotes wound healing

(Continued)

2682 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 349-6 Cytokines and Cytokine Receptors

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-26 IL-20R1/IL-10R2 TH1, TH17 T cells, synovial cells Epithelial cells Proinflammatory; induces cytokine production

IL-27 gp130t

wsx-1

Myeloid cells such as

macrophages and DCs

T cells Collaborates with other cytokines to activate T-cell

differentiation

IL-28A (IFN-λ2) IFN-λ receptor 1,

IL-28Rα, IL-10Rβ

Myeloid lineage cells; epithelial

cells

Epithelial cells Enhanced clearance of viral infections

IL-28B (IFN-λ3) IFN-λ receptor 1,

IL-28Rα, IL-10Rβ

Myeloid lineage cells; epithelial

cells

Epithelial cells Enhanced clearance of viral infections

IL-29 (IFN-λ1) IFN-λ receptor 1,

IL-28Rα, IL-10Rβ

Myeloid lineage cells; epithelial

cells

Epithelial cells Enhanced clearance of viral infections

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-31 IL-31RA/oncostatin MRβ Eosinophils, CD4 T cells Epithelial cells, monocytes Pruritis, proinflammatory

IL-32 (NK4) ? Monocytes, T cells, NK cells,

epithelial cells

Monocytes, macrophages,

bone marrow stroma

Angiogenesis, IL-2 production in bone marrow,

proinflammatory

IL-33 (NF-HEV;

IL-1 F11)

ST-2 Endothelial cells, epithelial

cells, fibroblasts, mucosal

epithelium

T cells, mast cells eosinophils,

basophils, ILC2s

Alarmin cytokine, proinflammatory

IL-34 (C16of77) CSF-1R, PTP-E, CD138 Neurons, Treg, myeloid cells Anti-inflammatory myeloid cell proliferation

IL-35 IL-12Rβ2/IL-12Rβ2, gp130/

gp130, IL-12Rb2/gp130

Tregs, Bregs Macrophages, T cells Prevents TH1 and TH17 proliferation; induced Treg/Breg

proliferation/anti-inflammatory

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

TH responses, proinflammatory

IL-38

IL-10 F10

IL-1R, IL-36R, IL-1RA PL1 Epithelial cells, B cells Epithelial cells, macrophages,

DCs, T cells, B cells, plasma cells

Blocks IL-36; anti-inflammatory

IL-39 ? Macrophages, DCs, B cells Neutrophils Proinflammatory

IL-40 ? B cells, bone marrow/stroma B cells Involved in IgA production, B-cell homeostasis and

development

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

IFN-β Type I interferon receptor All cells All cells 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

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; TH1

T-cell differentiation

TNF-α TNFrI, TNFrII Monocytes-macrophages, mast

cells, basophils, eosinophils,

NK cells, B cells, T cells,

keratinocytes, fibroblasts,

thymic epithelial cells

All cells except erythrocytes Fever, anorexia, shock, capillary leak syndrome,

enhanced leukocyte cytotoxicity, enhanced

NK-cell function, acute phase protein synthesis,

proinflammatory cytokine induction

TNF-β TNFrI, TNFrII T cells, B cells All cells except erythrocytes Cell cytotoxicity, lymph node and spleen development

LT-β LTβR T cells All cells except erythrocytes Cell cytotoxicity, normal lymph node development

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-CSF GM-CSFr, common β T cells, monocytesmacrophages, fibroblasts,

endothelial cells, thymic

epithelial cells

Monocytes-macrophages,

neutrophils, eosinophils,

fibroblasts, endothelial cells

Regulates myelopoiesis; enhances macrophage

bactericidal and tumoricidal activity; mediator of

dendritic cell maturation and function; upregulates

NK-cell function; clinical use in reversing neutropenia

after cytotoxic chemotherapy

M-CSF M-CSFr (c-fms

protooncogene)

Fibroblasts, endothelial cells,

monocytes-macrophages, T

cells, B cells, epithelial cells

including thymic epithelium

Monocytes-macrophages Regulates monocyte-macrophage production and

function

(Continued)

(Continued)

Introduction to the Immune System

2683CHAPTER 349

TABLE 349-6 Cytokines and Cytokine Receptors

CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY

LIF LIFr-α; gp130 Activated T cells, bone marrow

stromal cells, thymic epithelium

Megakaryocytes, monocytes,

hepatocytes, possibly

lymphocyte subpopulations

Induces hepatic acute-phase protein production;

stimulates macrophage differentiation; promotes

growth of myeloma cells and hematopoietic

progenitors; stimulates thrombopoiesis

OSM OSMr; LIFr; gp130 Activated monocytesmacrophages and T cells, bone

marrow stromal cells, some

breast carcinoma cell lines,

myeloma cells

Neurons, hepatocytes,

monocytes-macrophages,

adipocytes, alveolar epithelial

cells, embryonic stem cells,

melanocytes, endothelial cells,

fibroblasts, myeloma cells

Induces hepatic acute-phase protein production;

stimulates macrophage differentiation; promotes

growth of myeloma cells and hematopoietic

progenitors; stimulates thrombopoiesis; stimulates

growth of Kaposi’s sarcoma cells

SCF SCFr (c-kit

protooncogene)

Bone marrow stromal cells and

fibroblasts

Embryonic stem cells, myeloid

and lymphoid precursors, mast

cells

Stimulates hematopoietic progenitor cell growth, mast

cell growth; promotes embryonic stem cell migration

TGF-β (3

isoforms)

Type I, II, III TGF-β

receptor

Most cell types Most cell types Downregulates T-cell, macrophage, and granulocyte

responses; stimulates synthesis of matrix proteins;

stimulates angiogenesis

Lymphotactin/

SCM-1

XCR1 NK cells, mast cells, doublenegative thymocytes, activated

CD8+ T cells

T cells, NK cells Chemoattractant for lymphocytes; only known

chemokine of C class

MCP-1 CCR2 Fibroblasts, smooth-muscle

cells, activated PBMCs

Monocytes-macrophages, NK

cells, memory T cells, basophils

Chemoattractant for monocytes, activated memory

T cells, and NK cells; induces granule release from

CD8+ T cells and NK cells; potent histamine-releasing

factor for basophils; suppresses proliferation of

hematopoietic precursors; regulates monocyte

protease production

MCP-2 CCR1, CCR2 Fibroblasts, activated PBMCs Monocytes-macrophages, T

cells, eosinophils, basophils,

NK cells

Chemoattractant for monocytes, memory and naïve T

cells, eosinophils, ?NK cells; activates basophils and

eosinophils; regulates monocyte protease production

MCP-3 CCR1, CCR2 Fibroblasts, activated PBMCs Monocytes-macrophages, T

cells, eosinophils, basophils,

NK cells, dendritic cells

Chemoattractant for monocytes, memory and naïve T

cells, dendritic cells, eosinophils, ?NK cells; activates

basophils and eosinophils; regulates monocyte

protease production

MCP-4 CCR2, CCR3 Lung, colon, small intestinal

epithelial cells, activated

endothelial cells

Monocytes-macrophages, T

cells, eosinophils, basophils

Chemoattractant for monocytes, T cells, eosinophils,

and basophils

Eotaxin CCR3 Pulmonary epithelial cells,

heart

Eosinophils, basophils Potent chemoattractant for eosinophils and basophils;

induces allergic airways disease; acts in concert

with IL-5 to activate eosinophils; antibodies to eotaxin

inhibit airway inflammation

TARC CCR4 Thymus, dendritic cells,

activated T cells

T cells, NK cells Chemoattractant for T and NK cells

MDC CCR4 Monocytes-macrophages,

dendritic cells, thymus

Activated T cells Chemoattractant for activated T cells; inhibits infection

with T-cell tropic HIV-1

MIP-1α CCR1, CCR5 Monocytes-macrophages, T

cells

Monocytes-macrophages, T

cells, dendritic cells, NK cells,

eosinophils, basophils

Chemoattractant for monocytes, T cells, dendritic

cells, and NK cells, and weak chemoattractant

for eosinophils and basophils; activates NK-cell

function; suppresses proliferation of hematopoietic

precursors; necessary for myocarditis associated

with coxsackievirus infection; inhibits infection with

monocytotropic HIV-1

MIP-1β CCR5 Monocytes-macrophages, T

cells

Monocytes-macrophages, T

cells, NK cells, dendritic cells

Chemoattractant for monocytes, T cells, and NK cells;

activates NK-cell function; inhibits infection with

monocytotropic HIV-1

RANTES CCR1, CCR2, CCR5 Monocytes-macrophages, T

cells, fibroblasts, eosinophils

Monocytes-macrophages, T

cells, NK cells, dendritic cells,

eosinophils, basophils

Chemoattractant for monocytes-macrophages, CD4+,

CD45Ro+ T cells, CD8+ T cells, NK cells, eosinophils,

and basophils; induces histamine release from

basophils; inhibits infections with monocytotropic HIV-1

LARC/MIP-3α/

Exodus-1

CCR6 Dendritic cells, fetal liver cells,

activated T cells

T cells, B cells Chemoattractant for lymphocytes

ELC/MIP-3β CCR7 Thymus, lymph node, appendix Activated T cells and B cells Chemoattractant for B and T cells; receptor

upregulated on EBV-infected B cells and HSV-infected

T cells

I-309/TCA-3 CCR8 Activated T cells Monocytes-macrophages, T

cells

Chemoattractant for monocytes; prevents

glucocorticoid-induced apoptosis in some T-cell lines

SLC/TCA-4/

Exodus-2

CCR7 Thymic epithelial cells, lymph

node, appendix, and spleen

T cells Chemoattractant for T lymphocytes; inhibits

hematopoiesis

DC-CK1/PARC Unknown Dendritic cells in secondary

lymphoid tissues

Naïve T cells May have a role in induction of immune responses

(Continued)

(Continued)

2684 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 349-6 Cytokines and Cytokine Receptors

CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY

TECK CCR9 Dendritic cells, thymus, liver,

small intestine

T cells, monocytesmacrophages, dendritic cells

Thymic dendritic cell–derived cytokine, possibly

involved in T-cell development

GRO-α/MGSA CXCR2 Activated granulocytes,

monocyte-macrophages, and

epithelial cells

Neutrophils, epithelial cells,

?endothelial cells

Neutrophil chemoattractant and activator; mitogenic

for some melanoma cell lines; suppresses proliferation

of hematopoietic precursors; angiogenic activity

GRO-β/MIP-2α CXCR2 Activated granulocytes and

monocyte-macrophages

Neutrophils and ?endothelial

cells

Neutrophil chemoattractant and activator; angiogenic

activity

NAP-2 CXCR2 Platelets Neutrophils, basophils Derived from platelet basic protein; neutrophil

chemoattractant and activator

IP-10 CXCR3 Monocytes-macrophages,

T cells, fibroblasts, endothelial

cells, epithelial cells

Activated T cells, tumorinfiltrating lymphocytes,

?endothelial cells, ?NK cells

IFN-γ-inducible protein that is a chemoattractant for

T cells; suppresses proliferation of hematopoietic

precursors

MIG CXCR3 Monocytes-macrophages,

T cells, fibroblasts

Activated T cells, tumorinfiltrating lymphocytes

IFN-γ-inducible protein that is a chemoattractant for

T cells; suppresses proliferation of hematopoietic

precursors

SDF-1 CXCR4 Fibroblasts T cells, dendritic cells,

?basophils, ?endothelial cells

Low-potency, high-efficacy T-cell chemoattractant;

required for B lymphocyte development; prevents

infection of CD4+, CXCR4+ cells by T-cell tropic

HIV-1

Fractalkine CX3CR1 Activated endothelial cells NK cells, T cells,

monocytes-macrophages

Cell-surface chemokine/mucin hybrid molecule that

functions as a chemoattractant, leukocyte activator,

and cell adhesion molecule

PF-4 Unknown Platelets, megakaryocytes Fibroblasts, endothelial cells Chemoattractant for fibroblasts; suppresses

proliferation of hematopoietic precursors; inhibits

endothelial cell proliferation and angiogenesis

Abbreviations: B7-1, CD80; B7-2, CD86; Breg, regulatory B cells; CCR, CC-type chemokine receptor; CXCR, CXC-type chemokine receptor; DC, dendritic cell; DC-CK,

dendritic cell chemokine; EBV, Epstein-Barr virus; ELC, EB11 ligand chemokine (MIP-1b); G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage

colony-stimulating factor; GRP, growth-related peptide; HSV, herpes simplex virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IP-10, IFN-γ-inducible protein-10;

LARC, liver- and activation-regulated chemokine; LIF, leukemia inhibitory factor; MCP, monocyte chemotactic protein; M-CSF, macrophage colony-stimulating factor; MDC,

macrophage-derived chemokine; MGSA, melanoma growth-stimulating activity; MHC, major histocompatibility complex; MIG, monokine induced by IFN-γ; MIP, macrophage

inflammatory protein; NAP, neutrophil-activating protein; NK, natural killer; OSM, oncostatin M; PARC, pulmonary- and activation-regulated chemokine; PBMC, peripheral

blood mononuclear cells; PF, platelet factor; RANTES, regulated on activation, normally T cell–expressed and –secreted; SCF, stem cell factor; SDF, stromal cell–derived

factor; SLC, secondary lymphoid tissue chemokine; TARC, thymus- and activation-regulated chemokine; TCA, T-cell activation protein; TECK, thymus-expressed chemokine;

TGF, transforming growth factor; TH1 and TH2, helper T cell subsets; TNF, tumor necrosis factor; Treg, regulatory T cells; VCAM, vascular cell adhesion

molecule.

Sources: Data from JS Sundy et al: Appendix B, in Inflammation, Basic Principles and Clinical Correlates, 3rd ed, J Gallin, R Snyderman (eds). Philadelphia, Lippincott

Williams and Wilkins, 1999; J Ye et al: Frontiers in Pharmacology 11; HM Lazear et al: Immunity 43: 15, 2015; J Catalan-Dibene et al: J Interferon and Cytokine Research 38:

423, 2018.

effectors of innate immune responses (Fig. 349-2). Unchecked accumulation and activation of granulocytes can lead to host tissue damage,

as seen in neutrophil- and eosinophil-mediated systemic necrotizing

vasculitis. Granulocytes are derived from stem cells in bone marrow.

Each type of granulocyte (neutrophil, eosinophil, or basophil) is

derived from a different subclass of progenitor cell that is stimulated to

proliferate by colony-stimulating factors (Table 349-6). During terminal maturation of granulocytes, class-specific nuclear morphology and

cytoplasmic granules appear that allow for histologic identification of

granulocyte type.

Neutrophils express Fc receptor IIIa for IgG (CD16a) as well as

receptors for activated complement components (C3b or CD35). Upon

interaction of neutrophils with antibody-coated (opsonized) bacteria

or immune complexes, azurophilic granules (containing myeloperoxidase, lysozyme, elastase, and other enzymes) and specific granules

(containing lactoferrin, lysozyme, collagenase, and other enzymes) are

released, and microbicidal superoxide radicals (O2

–

) are generated at

the neutrophil surface. The generation of superoxide leads to inflammation by direct injury to tissue and by alteration of macromolecules

such as collagen and DNA.

Eosinophils are potent cytotoxic effector cells for various parasitic

organisms. In Nippostrongylus brasiliensis helminth infection, eosinophils are important cytotoxic effector cells for removal of these

parasites. Key to regulation of eosinophil cytotoxicity to N. brasiliensis worms are antigen-specific T helper cells that produce IL-4, thus

providing an example of regulation of innate immune responses by

adaptive immunity antigen-specific T cells. Intracytoplasmic contents

of eosinophils, such as major basic protein, eosinophil cationic protein,

and eosinophil-derived neurotoxin, are capable of directly damaging

tissues and may be responsible in part for the organ system dysfunction

in the hypereosinophilic syndromes (Chap. 64). Because the eosinophil

granule contains anti-inflammatory types of enzymes (histaminase,

arylsulfatase, phospholipase D), eosinophils may homeostatically

downregulate or terminate ongoing inflammatory responses.

Basophils and tissue mast cells are potent reservoirs of cytokines

such as IL-4 and can respond to bacteria and viruses with antipathogen cytokine production through multiple TLRs expressed on their

surface. Mast cells and basophils can also mediate immunity through

the binding of antipathogen antibodies. This is a particularly important host defense mechanism against parasitic diseases. Basophils

express high-affinity surface receptors for IgE (FcεRII) (CD23) and,

upon cross-linking of basophil-bound IgE by antigen, can release

histamine, eosinophil chemotactic factor of anaphylaxis, and neutral

protease—all mediators of allergic immediate (anaphylaxis) hypersensitivity responses. In addition, basophils express surface receptors for

activated complement components (C3a, C5a), through which mediator release can be directly affected. Thus, basophils, like most cells

of the immune system, can be activated in the service of host defense

against pathogens, or they can be activated for mediation release and

cause pathogenic responses in allergic and inflammatory diseases. For

further discussion of tissue mast cells, see Chap. 354.

The Complement System The complement system, an important

soluble component of the innate immune system, is a series of plasma

enzymes, regulatory proteins, and proteins that are activated in a cascading fashion, resulting in cell lysis. There are four pathways of the

complementsystem: the classic activation pathway activated by antigen/

antibody immune complexes, the MBL (a serum collectin) activation

(Continued)

Introduction to the Immune System

2685CHAPTER 349

pathway activated by microbes with terminal mannose groups, the

alternative activation pathway activated by microbes or tumor cells,

and the terminal pathway that is common to the first three pathways

and leads to the membrane attack complex that lyses cells (Fig. 349-5).

The series of enzymes of the complement system are serine proteases.

Activation of the classic complement pathway via immune complex

binding to C1q links the innate and adaptive immune systems via specific antibody in the immune complex. The alternative complement

activation pathway is antibody-independent and is activated by binding of C3 directly to pathogens and “altered self ” such as tumor cells. In

the renal glomerular inflammatory disease IgA nephropathy, IgA activates the alternative complement pathway and causes glomerular damage and decreased renal function. Activation of the classic complement

pathway via C1, C4, and C2 and activation of the alternative pathway

via factor D, C3, and factor B both lead to cleavage and activation of

C3. C3 activation fragments, when bound to target surfaces such as

bacteria and other foreign antigens, are critical for opsonization (coating by antibody and complement) in preparation for phagocytosis. The

MBL pathway substitutes MBL-associated serine proteases (MASPs) 1

and 2 for C1q, C1r, and C1s to activate C4. The MBL activation pathway is activated by mannose on the surface of bacteria and viruses.

The three pathways of complement activation all converge on the

final common terminal pathway. C3 cleavage by each pathway results

in activation of C5, C6, C7, C8, and C9, resulting in the membrane

attack complex that physically inserts into the membranes of target

cells or bacteria and lyses them.

Thus, complement activation is a critical component of innate

immunity for responding to microbial infection. The functional consequences of complement activation by the three initiating pathways and

the terminal pathway are shown in Fig. 349-5. In general, the cleavage

products of complement components facilitate microbe or damaged

cell clearance (C1q, C4, C3), promote activation and enhancement

of inflammation (anaphylatoxins, C3a, C5a), and promote microbe

or opsonized cell lysis (membrane attack complex). Deficiencies of

early complement components C1, C4, or C2 can be associated with

autoimmune disorders or with encapsulated bacterial infections like

Streptococcus pneumoniae. Deficiencies of late complement components (C5-C9) are associated with increased Neisseria infections.

TABLE 349-7 CC, CXC1

, CX3

, C1

, and XC Families of Chemokines and Chemokine Receptors

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

CCR2 CCL2 (MCP-1), CCL8 (MCP-2), CCL7

(MCP-3), CCL13 (MCP-4), CCL16 (HCC4)

Monocytes, dendritic cells (immature),

memory T cells

Atherosclerosis, rheumatoid arthritis, multiple sclerosis,

resistance to intracellular pathogens, type 2 diabetes

mellitus

CCR3 CCL11 (eotaxin), CCL13 (eotaxin-2), CCL7

(MCP-3), CCL5 (RANTES), CCL8 (MCP-2),

CCL13 (MCP-4)

Eosinophils, basophils, mast cells, TH2,

platelets

Allergic asthma and rhinitis

CCR4 CCL17 (TARC), CCL22 (MDC) T cells (TH2), dendritic cells (mature),

basophils, macrophages, platelets

Parasitic infection, graft rejection, T-cell homing to skin

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

CCR6 CCL20 (MIP-3α, LARC) T cells (T regulatory and memory), B

cells, dendritic cells

Mucosal humoral immunity, allergic asthma, intestinal

T-cell homing

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

CCR8 CCL1 (1309) T cells (TH2), monocytes, dendritic cells Dendritic cell migration to lymph node, type 2 cellular

immunity, granuloma formation

CCR9 CCL25 (TECK) T cells, IgA+ plasma cells Homing of T cells and IgA+ plasma cells to the intestine,

inflammatory bowel disease

CCR10 CCL27 (CTACK), CCL28 (MEC) T cells T-cell homing to intestine and skin

CXCR1 CXCL8 (interleukin-8), CXCL6 (GCP2) Neutrophils, monocytes Inflammatory lung disease, COPD

CXCR2 CXCL8, CXCL1 (GROα), CXCL2 (GROα),

CXCL3 (GROα), CXCL5 (ENA-78), CXCL6

Neutrophils, monocytes, microvascular

endothelial cells

Inflammatory lung disease, COPD, angiogenic for tumor

growth

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

CXCR3-B CXCL4 (PF4), CXCL9 (MIG), CXCL10 (IP10), CXCL11 (I-TAC)

Microvascular endothelial cells,

neoplastic cells

Angiostatic for tumor growth

CXCR4 CXCL12 (SDF-1) Widely expressed HIV-1 co-receptor (T cell–tropic), tumor metastases,

hematopoiesis

CXCR5 CXCL13 (BCA-1) B cells, follicular helper T cells Formation of B-cell follicles

CXCR6 CXCL16 (SR-PSOX) CD8+ T cells, natural killer cells, and

memory CD4+ T cells

Inflammatory liver disease, atherosclerosis (CXCL16)

CX3

CR1 CX3CL1 (fractalkine) Macrophages, endothelial cells,

smooth-muscle cells

Atherosclerosis

XCR1 XCL1 (lymphotactin), XCL2 T cells, natural killer cells Rheumatoid arthritis, IgA nephropathy, tumor response

Abbreviations: BCA-1, B-cell chemoattractant 1; COPD, chronic obstructive pulmonary disease; CTACK, cutaneous T cell–attracting chemokine; ELC, Epstein-Barr I1-ligand

chemokine; ENA, epithelial cell–derived neutrophil-activating peptide; GCP, granulocyte chemotactic protein; GRO, growth-regulated oncogene; HCC, hemofiltrate

chemokine; IP-10, interferon inducible 10; I-TAC, interferon-inducible T-cell alpha chemoattractant; LARC, liver- and activation-regulated chemokine; MCP, monocyte

chemoattractant protein; MDC, macrophage-derived chemokine; MEC, mammary-enriched chemokine; MIG, monokine induced by interferon-γ; MIP, macrophage

inflammatory protein; PF, platelet factor; SDF, stromal cell–derived factor; SLC, secondary lymphoid-tissue chemokine; SR-PSOX, scavenger receptor for phosphatidylserinecontaining oxidized lipids; TARC, thymus- and activation-regulated chemokine; TECK, thymus-expressed chemokine; TH2, type 2 helper T cells.

Source: From IF Charo, RM Ranshohoff: The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610, 2006. Copyright © (2006)

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

2686 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

FIGURE 349-3 Development and function of innate lymphoid cells (ILCs). A. ILC development, mainly based on mouse ILC differentiation paths, is schematized. ILCs develop

from common innate lymphoid progenitors (CILPs), which themselves differentiate from common lymphoid progenitors (CLPs). CILPs can differentiate into natural killer (NK)

cell precursor (NKP) cells or into common helper innate lymphoid progenitors (CHILPs), which themselves give rise to lymphoid tissue inducer progenitors (LTiPs) and innate

lymphoid cell precursors (ILCPs). LTiPs differentiate into lymphoid tissue inducers (LTis) and ILCPs into ILC1, ILC2, or ILC3. Each stage of differentiation is dependent on the

expression of the indicated transcription factors: NFIL3 (nuclear factor IL-3 induced), Id2 (inhibitor of DNA binding 2), TOX (thymocyte selection-associated high mobility

group box protein), TCF-1 (T-cell factor 1), ETS1 (avian erythroblastosis virus E26 homolog-1), GATA3 (GATA binding protein 3), PLZF (promyelocytic leukemia zinc finger),

T-bet (T-box transcription factor), Eomes (eomesodermin), RUNX3 (runt-related transcription factor 3), RORα (RAR-related orphan receptor α), Bcl11b (B cell lymphoma/

leukemia 11B), Gfi1 (growth factor independent 1), RORγt (RAR-related orphan receptor γt), and AHR (Aryl hydrocarbon receptor). It has been shown in humans that ILC1

subsets may originate from precursors other than ILCPs, but the identity of these precursors remains unknown at this time. B. Some of the most well-known immune

functions of each ILC subset are shown: NK cells and ILC1s react to intracellular pathogens, such as viruses, and to tumors; ILC2s respond to large extracellular parasites

and allergens; ILC3s combat extracellular microbes, such as bacteria and fungi; and Lutes are involved in the formation of secondary lymphoid structures. For each ILC

subset, effector molecules that can be produced upon activation are indicated AREG, amphiregulin; RANK, receptor activation of nuclear factor kB; RANK-L, RANK-ligand.

(Reproduced with permission from E Vivier et al: Innate lymphoid cells: 10 years on. Cell 174:1054, 2018.)

NFIL3

ID2

TOX

TCF-1

ETS1

ROR α

Bci11B

GATA3

GFI1

T-BET

NFIL3

RUNX3

ROR αT

AHR

ID2

ROR αT

TOX

ID2

GATA3

PLZF

TOX

NFIL3

ID2

ETS1

T-BET

EOMES

CLP

NKP

NK

A

ILC1 ILC2

ILCP

CHILP

CILP

ILC3 LTi

LTiP

■ CYTOKINES

Cytokines are soluble proteins produced by a wide variety of cell types

(Tables 349-6 and 349-7). They are critical for both normal innate and

adaptive immune responses, and their expression may be perturbed in

most immune, inflammatory, and infectious disease states.

Cytokines are involved in the regulation of the growth, development, and activation of immune system cells and in the mediation of

the inflammatory response. In general, cytokines are characterized by

considerable redundancy; different cytokines have similar functions.

In addition, many cytokines are pleiotropic in that they are capable of

acting on many different cell types. This pleiotropism results from the

expression on multiple cell types of receptors for the same cytokine (see

below), leading to the formation of “cytokine networks.” The action of

cytokines may be (1) autocrine when the target cell is the same cell that

secretes the cytokine, (2) paracrine when the target cell is nearby, and

(3) endocrine when the cytokine is secreted into the circulation and acts

distal to the source.

Cytokines have been named based on presumed targets or based

on presumed functions. Those cytokines that are thought to primarily

target leukocytes have been named IL-1, -2, -3, etc. Many cytokines that

Introduction to the Immune System

2687CHAPTER 349

NK

Stimuli Mediators Immune function

ILC1

ILC2

ILC3

LTi

IFN-γ

Granzymes

Perforin

IL-4

IL-5

IL-13

IL-9

AREG

RANK

Lymphotoxin

TNF

IL-17

IL-22

IL-22

IL-17

GM-CSF

Lymphotoxin

Type 1 immunity

(macrophage activation,

cytotoxicity)

Type 2 immunity

(alternative macrophage

activation)

Formation of secondary

lymphoid structures

Type 3 immunity

(phagocytosis,

antimicrobial peptides)

Tumors, intracellular

microbes (virus, bacteria,

parasites)

Large extracellular

parasites and allergens

Mesenchymal

organizer cells

(retinoic acid,

CXCL13, RANK-L)

Extracellular microbes

(bacteria, fungi)

B

FIGURE 349-3 (Continued)

TABLE 349-8 Association of KIRS with Disease

DISEASE KIR ASSOCIATION OBSERVATION

Psoriatic arthritis KIR2DS1/KIR2DS2; HLA-Cw group homozygosity Susceptibility

Spondylarthritides Increased KIR3DL2 expression

Interaction of HLA-B27 homodimers with KIR3DL1/KIR3DL2;

independent of peptide

May contribute to disease pathology

May contribute to disease pathogenesis

Ankylosing spondylitis KIR3DL1/3DS1; HLA-B27 genotypes Susceptibility

Rheumatoid vasculitis KIR2DS2; HLA-Cw*03

Increased KIR2L2/2DS2 in patients with extraarticular

manifestations

Susceptibility

Clinical manifestations may have different genetic

backgrounds with respect to KIR genotype

Rheumatoid arthritis Decreased KIR2DS1/3DS1 in patients without bone erosions

KIR2DS4; HLA-Cw4

Susceptibility

Susceptibility

Scleroderma KIR2DS2+/KIR2DL2– Susceptibility

Behçet’s disease Altered KIR3DL1 expression Associated with severe eye disease

Psoriasis vulgaris 2DS1; HLA-Cw*06

2DS1; 2DL5; haplotype B

Susceptibility

Susceptibility

IDDM KIR2DS2; HLA-C1 Susceptibility

Type 1 diabetes KIR2DS2; HLA-C1 and no HLA-C2, no HLA-Bw4 Increased disease progression

Preeclampsia KIR2DL1 with fewer KIR2DS (mother); HLA-C2 (fetus) Increased disease progression

AIDS KIR3DS1; HLA-Bw4Ile80

KIR3DS1 homozygous; no HLA-Bw4Ile80

Decreased disease progression

Increased disease progression

HCV infection KIR2DL3 homozygous; HLA-C1 homozygous Decreased disease progression

Cervical neoplasia (HPV induced) KIR3DS1; HLA-C1 homozygous and no HLA-Bw4 Increased disease progression

Malignant melanoma KIR2DL2 and/or KIR2DL3; HLA-C1 Increased disease progression

Abbreviations: HCV, hepatitis C virus; HLA, human leukocyte antigen; HPV, human papillomavirus; IDDM, insulin-dependent diabetes mellitus; KIR, killer cell immunoglobulinlike receptor.

Source: Reproduced with permission from R Diaz-Pena et al: KIR genes and their role in spondyloarthropathies. Adv Exp Med Biol 649:286, 2009.

were originally described as having a certain function have retained

those names (e.g., granulocyte colony-stimulating factor [G-CSF]).

Cytokines belong in general to three major structural families: the

hematopoietin family; the TNF, IL-1, platelet-derived growth factor (PDGF), and transforming growth factor (TGF) β families; and

the CXC and C-C chemokine families. Chemokines are cytokines

that regulate cell movement and trafficking; they act through G

protein-coupled receptors and have a distinctive three-dimensional

structure. IL-8 is the only chemokine that early on was named an IL

(Table 349-6).