The immune system: innate and adaptive immunity

The innate immune system is phylogenetically ancient compared with the more evolved form of host defense existing only in vertebrates. The cellular effectors of the innate immune system consist of neutrophils, monocytes, macrophages, and natural killer (NK) cells, which are all characterized by specific phagocytic and killing activities, whereas complement components and cytokines represent the circulating effector proteins of the innate system.

Surface receptors on phagocytes are able to specifically recognize and interact with highly conserved structures of microbial pathogens that are not present in mammalian cells. The binding of microbial structures to these receptors triggers the cell to phagocytize the pathogen and cause the activated cells to produce several proinflammatory molecules. Thus, innate immunity not only represents an early effective defense mechanism against infection but also provides the alert to the presence of an infection against which a subsequent adaptive immune response has to be built up.

The main features of the adaptive immune system are (1) the ability to interface with microbes in the presence of a high level of molecular specificity, (2) to remember this interaction, and (3) to be able to respond more promptly and powerfully to subsequent exposures to the same microbe (ie, immunologic memory). In this regard, any element capable of being recognized by the adaptive immune system is called an antigen .

The cellular effectors are represented by lymphocytes, a heterogeneous cell group that consists of various subsets that are morphologically similar but functionally different.

Based on the presence of specific antigen receptors, lymphocytes are capable of recognizing either soluble or membrane-bound antigenic determinants by specific antigen receptors.

There are 2 main types of lymphocytes: (1) those that mature in the thymus, known as T (thymus) lymphocytes and (2) those that undergo their maturation in the bone marrow and are, therefore, known as B (bone marrow) lymphocytes. The latter produce antibodies and are responsible for humoral immunity. Their antigen receptors are membrane-bound antibodies that can recognize soluble antigens.

Induction of the immune response: how cells of the innate system recognize nonself proteins and become activated

The innate immune response relies on the recognition of evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs), through a limited number of germ line–encoded pattern recognition receptors (PRRs). Among them, the family of Toll-like receptors (TLRs) has been studied most extensively. The peculiarity of PAMPs is being tightly conserved among classes of pathogens and distinctly discernible from self. This feature allows the immune system to detect the presence of different microbial infections through a limited number of germ line–encoded PRRs. The surface of cells of the innate immune system (eg, macrophages and dendritic cells) present different classes of PPRs, which act as tissue sentinels through the continuous monitoring of peripheral tissues for the possible invasion of microbial pathogens. TLRs are recognized by having an extracellular leucine-rich repeat (LRR) domain and an intracellular Toll/interleukin 1 (IL-1) receptor (TIR) domain ( Fig. 1 ). To date, 10 TLRs have been identified in humans and each recognize distinct PAMPs derived from various microbial pathogens, including viruses, bacteria, fungi, and protozoa ( Table 1 ). Some TLRs (TLR-1, -2, -4, -5, -6, and -10) are expressed on the cell surface, whereas others (TLR-3, -7, -8, and -9) are located in intracellular compartments, including endosomes and lysosomes (see Fig. 1 ). Given their position, the former mainly recognize bacterial products unique to bacteria and not produced by the host, whereas the latter are specialized in recognition of nucleic acids. The PAMP binding to TLRs through the PAMP-TLR interaction causes receptor oligomerization, which triggers intracellular signal transduction, ultimately resulting in the generation of an antimicrobial proinflammatory response, which is also capable of involving and driving the adaptive branch of the immune system (see later discussion).

Localization and structure of cellular pattern recognition receptors. TLRs are membrane-bound receptors localized at the cellular or endosomal membranes. In addition, there are intracellular (cytosolic) receptors that function in the pattern recognition of bacterial and viral pathogens. Nucleotide-binding oligomerization domain (NOD)2/CARD15 and NALP3 belong to the NOD-like receptors (NLR) family. Most NLRs contain a LRR domain for PAMPs recognition, such as muramyl dipeptide (MDP) for NOD2/CARD15. Retinoic-acid-inducible gene I (RIG-I) represents an example of a class of intracellular sensors of viral nucleic acids grouped under the term of RIG-I–like receptors (RLRs). Thanks to its C-terminal helicase domain, RIG-I bind to viral RNA and become activated to transduce CARD-dependent signaling, ultimately resulting in an antiviral response mediated by type I interferon production.

In addition to the transmembrane receptors on the cell surface and in endosomal compartments, cells of the innate immune system also contain intracellular (cytosolic) receptors that function in the pattern recognition of viral and bacterial pathogens. These receptors include nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the intracellular sensors of viral nucleic acids, such as retinoic-acid-inducible gene I (RIG-I) or melanoma differentiation–associated gene 5, grouped under the term RIG-I-like receptors (RLRs) (see Fig. 1 ). NLRs are a large family of intracellular proteins with a common protein-domain organization but diversified functions. NOD and subfamilies are the most characterized among NLRs. The proteins of the NOD subfamily, NOD1 and NOD2, are both involved in sensing bacterial molecules derived from the synthesis and degradation of peptidoglycan. NOD1 recognizes diaminopimelic acid produced primarily by gram-negative bacteria, whereas NOD2 is activated by muramyl dipeptide (MDP), a component of both gram-positive and gram-negative bacteria.

The Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing family (NLRP) subfamily of NLRs consists of 14 members. Some of them are involved in the induction of the inflammatory response mediated by the IL-1 family of cytokines, which includes IL-1β and IL-18. These cytokines are synthesized as inactive precursors that need to be cleaved by proinflammatory caspases (ie, caspases 1, 4, and 5). These caspases are activated through a multiprotein complex known as the inflammasome (see later discussion). Most of the aforementioned PRRs are capable of sensing not only pathogens (namely through PAMPS) but also get activated/alerted by misfolded/glycated proteins or exposed hydrophobic portions of molecules released at high levels by injured cells, the so-called damage-associated molecular pattern (DAMP).

Dendritic cells (DCs) belong to the cell machinery driving innate immunity and are specialized in the processing and presentation of exogenous pathogen-derived antigens to T cells during the adaptive immune response at the level of secondary lymphoid organs. Thus, DCs should be considered as key players in bridging innate and adaptive immunity.

The recognition of microbial or viral products through the same PRR that are present on the surface of phagocytes triggers the migration of DCs to lymph nodes where they undergo functional maturation and start to express costimulatory molecules (eg, CD80, CD86, CD40, and antigen-presenting major histocompatibility complex [MHC] molecules) that enable them to function as antigen-presenting cells to T cells. DCs control many T-cell responses. For example, under the control of DCs, helper T cells (Th) acquire the capability to produce powerful cytokines that differentially regulate their tasks, defining functionally different subsets. Th1 cells mainly secrete interferon-γ (IFNγ) and activate macrophages to resist infection by facultative and obligate intracellular microbes; Th2 cells produce IL-4, IL-5, and IL-13 to mobilize white cells against helminths; and Th17 cells make IL-17 to mobilize phagocytes at the site of invasion of extracellular bacilli (see later discussion).

B lymphocytes constitute an interesting cell population sharing functional features common to both innate (ie, same PRR expression and antigen presenting function for T cells) and adaptive (ie, specific response to antigens and immunologic memory) immunity. B cells develop in the bone marrow, express cell surface immunoglobulins functioning as antigen receptors, and localize to secondary lymphoid organs and in low number in the circulation.

In order for B cells to become activated, a second signal is required in addition to the binding of the antigen receptor to its specific ligand. The second signal may be provided by the pathogen itself (thymus-independent [TI] antigens) or be delivered by an already-primed T cell (for thymus-dependent [TD] antigens). The so-called TI antigens are nonprotein antigens that elicit antibody production in athymic individuals. The most important TI antigens are polymeric polysaccharides or glycolipids present in the bacterial cell wall. These antigens induce maximal cross-linking of membrane immunoglobulins, resulting in B-cell activation without the necessity of T-cell help.

The functional interplay between T and B cells takes place in peripheral lymphoid organs (lymph nodes, spleen, mucosal immune system). In lymphoid organs, naïve B and T cells are anatomically compartmentalized and separated but, following an antigen-induced activation, are elicited to migrate toward one another. The recognition of the specific peptide-MHC complex on the surface of B cells cause Th cells to become activated and express the cell surface molecule CD40L, resulting in cytokine secretion. The link between CD40L (expressed on activated Th cells) and CD40 (constitutively expressed on B cells) leads to further activation of B cells, with the same mechanisms already described for DC.

Induction of the immune response: how cells of the innate system recognize nonself proteins and become activated

The innate immune response relies on the recognition of evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs), through a limited number of germ line–encoded pattern recognition receptors (PRRs). Among them, the family of Toll-like receptors (TLRs) has been studied most extensively. The peculiarity of PAMPs is being tightly conserved among classes of pathogens and distinctly discernible from self. This feature allows the immune system to detect the presence of different microbial infections through a limited number of germ line–encoded PRRs. The surface of cells of the innate immune system (eg, macrophages and dendritic cells) present different classes of PPRs, which act as tissue sentinels through the continuous monitoring of peripheral tissues for the possible invasion of microbial pathogens. TLRs are recognized by having an extracellular leucine-rich repeat (LRR) domain and an intracellular Toll/interleukin 1 (IL-1) receptor (TIR) domain ( Fig. 1 ). To date, 10 TLRs have been identified in humans and each recognize distinct PAMPs derived from various microbial pathogens, including viruses, bacteria, fungi, and protozoa ( Table 1 ). Some TLRs (TLR-1, -2, -4, -5, -6, and -10) are expressed on the cell surface, whereas others (TLR-3, -7, -8, and -9) are located in intracellular compartments, including endosomes and lysosomes (see Fig. 1 ). Given their position, the former mainly recognize bacterial products unique to bacteria and not produced by the host, whereas the latter are specialized in recognition of nucleic acids. The PAMP binding to TLRs through the PAMP-TLR interaction causes receptor oligomerization, which triggers intracellular signal transduction, ultimately resulting in the generation of an antimicrobial proinflammatory response, which is also capable of involving and driving the adaptive branch of the immune system (see later discussion).

Localization and structure of cellular pattern recognition receptors. TLRs are membrane-bound receptors localized at the cellular or endosomal membranes. In addition, there are intracellular (cytosolic) receptors that function in the pattern recognition of bacterial and viral pathogens. Nucleotide-binding oligomerization domain (NOD)2/CARD15 and NALP3 belong to the NOD-like receptors (NLR) family. Most NLRs contain a LRR domain for PAMPs recognition, such as muramyl dipeptide (MDP) for NOD2/CARD15. Retinoic-acid-inducible gene I (RIG-I) represents an example of a class of intracellular sensors of viral nucleic acids grouped under the term of RIG-I–like receptors (RLRs). Thanks to its C-terminal helicase domain, RIG-I bind to viral RNA and become activated to transduce CARD-dependent signaling, ultimately resulting in an antiviral response mediated by type I interferon production.

In addition to the transmembrane receptors on the cell surface and in endosomal compartments, cells of the innate immune system also contain intracellular (cytosolic) receptors that function in the pattern recognition of viral and bacterial pathogens. These receptors include nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the intracellular sensors of viral nucleic acids, such as retinoic-acid-inducible gene I (RIG-I) or melanoma differentiation–associated gene 5, grouped under the term RIG-I-like receptors (RLRs) (see Fig. 1 ). NLRs are a large family of intracellular proteins with a common protein-domain organization but diversified functions. NOD and subfamilies are the most characterized among NLRs. The proteins of the NOD subfamily, NOD1 and NOD2, are both involved in sensing bacterial molecules derived from the synthesis and degradation of peptidoglycan. NOD1 recognizes diaminopimelic acid produced primarily by gram-negative bacteria, whereas NOD2 is activated by muramyl dipeptide (MDP), a component of both gram-positive and gram-negative bacteria.

The Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing family (NLRP) subfamily of NLRs consists of 14 members. Some of them are involved in the induction of the inflammatory response mediated by the IL-1 family of cytokines, which includes IL-1β and IL-18. These cytokines are synthesized as inactive precursors that need to be cleaved by proinflammatory caspases (ie, caspases 1, 4, and 5). These caspases are activated through a multiprotein complex known as the inflammasome (see later discussion). Most of the aforementioned PRRs are capable of sensing not only pathogens (namely through PAMPS) but also get activated/alerted by misfolded/glycated proteins or exposed hydrophobic portions of molecules released at high levels by injured cells, the so-called damage-associated molecular pattern (DAMP).

Dendritic cells (DCs) belong to the cell machinery driving innate immunity and are specialized in the processing and presentation of exogenous pathogen-derived antigens to T cells during the adaptive immune response at the level of secondary lymphoid organs. Thus, DCs should be considered as key players in bridging innate and adaptive immunity.

The recognition of microbial or viral products through the same PRR that are present on the surface of phagocytes triggers the migration of DCs to lymph nodes where they undergo functional maturation and start to express costimulatory molecules (eg, CD80, CD86, CD40, and antigen-presenting major histocompatibility complex [MHC] molecules) that enable them to function as antigen-presenting cells to T cells. DCs control many T-cell responses. For example, under the control of DCs, helper T cells (Th) acquire the capability to produce powerful cytokines that differentially regulate their tasks, defining functionally different subsets. Th1 cells mainly secrete interferon-γ (IFNγ) and activate macrophages to resist infection by facultative and obligate intracellular microbes; Th2 cells produce IL-4, IL-5, and IL-13 to mobilize white cells against helminths; and Th17 cells make IL-17 to mobilize phagocytes at the site of invasion of extracellular bacilli (see later discussion).

B lymphocytes constitute an interesting cell population sharing functional features common to both innate (ie, same PRR expression and antigen presenting function for T cells) and adaptive (ie, specific response to antigens and immunologic memory) immunity. B cells develop in the bone marrow, express cell surface immunoglobulins functioning as antigen receptors, and localize to secondary lymphoid organs and in low number in the circulation.

In order for B cells to become activated, a second signal is required in addition to the binding of the antigen receptor to its specific ligand. The second signal may be provided by the pathogen itself (thymus-independent [TI] antigens) or be delivered by an already-primed T cell (for thymus-dependent [TD] antigens). The so-called TI antigens are nonprotein antigens that elicit antibody production in athymic individuals. The most important TI antigens are polymeric polysaccharides or glycolipids present in the bacterial cell wall. These antigens induce maximal cross-linking of membrane immunoglobulins, resulting in B-cell activation without the necessity of T-cell help.

The functional interplay between T and B cells takes place in peripheral lymphoid organs (lymph nodes, spleen, mucosal immune system). In lymphoid organs, naïve B and T cells are anatomically compartmentalized and separated but, following an antigen-induced activation, are elicited to migrate toward one another. The recognition of the specific peptide-MHC complex on the surface of B cells cause Th cells to become activated and express the cell surface molecule CD40L, resulting in cytokine secretion. The link between CD40L (expressed on activated Th cells) and CD40 (constitutively expressed on B cells) leads to further activation of B cells, with the same mechanisms already described for DC.