Box 6-1. Toll-like Receptors

Chapter 6 - Diseases of Immunity

Abul K. Abbas MD

General Features of the Immune System

Although vital to survival, the immune system is similar to the proverbial two-edged sword. On the one hand, immunodeficiency states render humans easy prey to infections and possibly

tumors; on the other hand, a hyperactive immune system may cause fatal disease, as in the case of an overwhelming allergic reaction to the sting of a bee. In yet another series of

derangements, the immune system may lose its normal capacity to distinguish self from non-self, resulting in immune reactions against one's own tissues and cells (autoimmunity). This

chapter considers diseases caused by too little immunity as well as those resulting from too much immunologic reactivity. We also consider amyloidosis, a disease in which an abnormal

protein, derived in some cases from fragments of immunoglobulins, is deposited in tissues. First, we review some advances in the understanding of innate and adaptive immunity and

lymphocyte biology, then give a brief description of the histocompatibility genes because their products are relevant to several immunologically mediated diseases and to the rejection of

transplants.

INNATE AND ADAPTIVE IMMUNITY

The physiologic function of the immune system is to protect individuals from infectious pathogens. The mechanisms that are responsible for this protection fall into two broad categories

( Fig. 6-1 ). Innate immunity (also called natural, or native, immunity) refers to defense mechanisms that are present even before infection and have evolved to specifically recognize microbes

and protect multicellular organisms against infections. Adaptive immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by (adapt to) microbes and

are capable of also recognizing nonmicrobial substances, called antigens. Innate immunity is the first line of defense, because it is always ready

Figure 6-1Innate and adaptive immunity. The principal mechanisms of innate immunity and adaptive immunity are shown.

Box 6-1. Toll-like Receptors

The Toll-like receptors (TLRs) are membrane proteins that recognize a variety of microbe-derived molecules and stimulate innate immune responses against the microbes. The first protein

to be identified in this family was the Drosophila Toll protein, which is involved in establishing the dorsal-ventral axis during embryogenesis of the fly, as well as mediating antimicrobial

responses. Ten different mammalian TLRs have been identified based on sequence homology to Drosophila Toll, and they are named TLR1-10. All these receptors contain leucine-rich

repeats flanked by characteristic cysteine-rich motifs in their extracellular regions, and a conserved signaling domain in their cytoplasmic region that is also found in the cytoplasmic tails

of the IL-1 and IL-18 receptors and is called the Toll/IL-1 receptor (TIR) domain. The TLRs are expressed on many different cell types that participate in innate immune responses,

including macrophages, dendritic cells, neutrophils, NK cells, mucosal epithelial cells, and endothelial cells.

Mammalian TLRs are involved in responses to widely divergent types of molecules that are commonly expressed by microbial but not mammalian cells (see Figure ). Some of the

microbial products that stimulate TLRs include Gram-negative bacterial lipopolysaccharide (LPS), Gram-positive bacterial peptidoglycan, bacterial lipoproteins, the bacterial flagellar

protein flagellin, heat shock protein 60, unmethylated CpG DNA motifs (found in many bacteria), and double-stranded RNA (found in RNA viruses). The specificity of TLRs for microbial

products is dependent on associations between different TLRs and non-TLR adapter molecules. For instance, LPS first binds to soluble LPS-binding protein (LBP) in the blood or

extracellular fluid, and this complex serves to facilitate LPS binding to CD14, which exists as both a soluble plasma protein and a glycophosphatidylinositol-linked membrane protein on

most cells. Once LPS binds to CD14, LBP dissociates, and the LPS-CD14 complex physically associates with TLR4. An additional extracellular accessory protein, called MD2, also binds

to the complex with CD14. LPS, CD14, and MD2 are all required for efficient LPS-induced signaling, but it is not yet clear if direct physical interaction of LPS with TLR4 is necessary.

Signaling by TLRs results in the activation of transcription factors, notably NF-kB (see Figure). Ligand binding to the TLR at the cell surface leads to recruitment of cytoplasmic signaling

molecules, the first of which is the adapter protein MyD88. A kinase called IL-1 receptor associated kinase (IRAK) is recruited into the signaling complex. IRAK undergoes

autophosphorylation, dissociates from MyD88, and activates another signaling molecule, called TNF-receptor (TNF-R) associated factor-6 (TRAF-6). TRAF-6 then activates the I-kB

kinase cascade, leading to activation of the NF-kB transcription factor. In some cell types certain TLRs also engage other signaling pathways, such as the MAP kinase cascade, leading to

activation of the AP-1 transcription factor. Some TLRs may use adapter proteins other than MyD88. The relative importance of these various pathways of TLR signaling, and the way the

"choice" of pathways is made, are not well understood.

The genes that are expressed in response to TLR signaling encode proteins important in many different components of innate immune responses. These include inflammatory cytokines

(TNF, IL-1, and IL-12), endothelial adhesion molecules (E-selectin), and proteins involved in microbial killing mechanisms (inducible nitric oxide synthase). The particular genes

expressed will depend on the responding cell type.

Figure 6-A, Different TLRs are involved in responses to different microbial products. B, Signaling by a prototypic TLR, TLR4, in response to bacterial LPS. An adapter protein links the

TLR to a kinase, which activates transcription factors such as NF-kB and AP-1. TIR, Toll/IL-1 receptor domain.

of innate immunity, providing protection against inhaled microbes.

The adaptive immune system consists of lymphocytes and their products, including antibodies. The receptors of lymphocytes are much more diverse than those of the innate immune

system, but lymphocytes are not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances. In the remainder of this introductory section we

focus on lymphocytes and the reactions of the adaptive immune system.

Date: 2016-04-22; view: 620