Immune system and host defense mechanisms

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Immune system and host defense mechanisms

“Remarkable adaptations . . . allow a genetically and antigenically disparate conceptus to develop in direct contact with a fully competent maternal immune system.”100 Why doesn’t the mother reject the fetus and placenta? Knowledge of maternal, fetal, and neonatal immune physiology and understanding of the immune relationship between a mother and her fetus are still evolving. Current theories regarding this question—along with alterations in host defense mechanisms in the mother and neonate and implications for clinical practice—are examined in this chapter.

The immune system is made up of organs and specialized cells whose primary purpose is to defend the body from foreign substances (antigens) that may cause tissue injury or disease. These defense mechanisms consist of nonspecific and specific factors. Nonspecific factors include physical and biochemical barriers including skin and mucosal barriers, bone marrow, lymphoid tissue, digestive enzymes, pH, temperature, proteins, and enzymes such as lysozyme, transferrin, and interferon. Specific factors include cellular and humoral components that respond to foreign substances. In addition, individual genetic susceptibilities affect both nonspecific factors and specific factors. Nonspecific and specific factors make up two arms of the immune response—the innate (also known as natural or native immunity) and the adaptive (also known as specific or acquired immunity) (Table 13-1). Mechanisms of innate and adaptive immunity work cooperatively through complex interactions to prevent, control, and eradicate foreign antigens in the body without doing harm to the host. Host immune mechanisms and terminology are summarized in Table 13-2 and Figures 13-1 and 13-2. Innate and adaptive immunity are summarized in Boxes 13-1 and 13-2 on page 446. Roles of cytokines (interleukins and interferons) in innate and adaptive immunity are summarized in Table 13-3.

BOX 13-1   Overview of Innate Immunity

The innate immune response, which includes inflammation, lysis of an antigen’s cell membrane, and phagocytosis (see Figure 13-1) is the first-line defense mechanism that comes into play after exposure to a foreign antigen.1,107 The innate immune response also has a crucial role in the activation of adaptive immune responses (see Figure 13-2). Innate immunity involves nonspecific inborn responses to a foreign antigen that are activated the first time the antigen is encountered. These defense mechanisms occur rapidly and only in response to microbes, not to noninfectious substances.1 Important characteristics of innate immunity include the following: (1) a prior exposure to the antigen is not required for a response to occur; (2) repeated exposures to an antigen over time will not alter the host’s innate immune response (i.e., immune responses do not become more vigorous); and (3) the ability to recognize molecular patterns shared by groups of microbes, but there is an inability to recognize fine distinctions between the microbes.1 Innate immunity involves physical (e.g., epithelia, mucous membranes, secretions) and biochemical barriers.

Primary effector cells of an innate immune response are polymorphonuclear neutrophils, macrophages, monocytes, mast cells, and natural killer (NK) cells (a T-lymphocyte subpopulation).107 In addition, toll-like receptors (TLRs) on cell surfaces (responsible for recognizing the molecular patterns of microbial products), endothelial cells, circulating factors (e.g., complement and acute phase proteins such as C-reactive protein), and cytokines and chemokines, which are secreted by macrophages and other cells, are actively involved in mediating the innate immune response and engaging the adaptive immune response (see Figures 13-1, 13-2, and 13-3).1,107

TLRs sense molecular patterns of pathogens and induce expression of cytokines and chemokines to activate defensive cells.111 Recognition of molecular patterns occurs via pattern recognition receptors (PRRs). PRRs are found on cell surfaces, in intracellular vesicles, or in the cytoplasm. PRRs can recognize damaging molecular patterns such as cytokines, intracellular proteins, substances released by damaged cells, and pathogen-associated molecular patterns.180 PRRs on TLRs “allow either the extracellular or liposomal (or endosomal) recognition of a wide range of microbes”107 or via nucleotide binding oligomerization domain (NOD) proteins which are “cytoplasm bound receptors that facilitate responses to invasive intracellular bacteria.”107, p.92 Pathogens bind to TLR and other receptors on monocytes and macrophages, initiating a complement cascade with release of prostaglandins (which mediate fever with bacterial pathogens). The transcription factor NF-ΚB is released, which stimulates synthesis and release of both proinflammatory (such as IL-1B, IL-6, and TNF-α) and antiinflammatory cytokines (such as IL-1 and IL-10).151

BOX 13-2   Overview of Adaptive Immunity

Adaptive immunity is the development of a protective response to a specific foreign antigen that has been processed and presented by the innate system, and the establishment of an immunologic memory of that response.107 There are six distinct characteristics of an adaptive immune response: (1) specificity (the ability to specifically respond to a distinct antigen or a part of an antigen); (2) diversity (the ability to respond to a wide variety of antigens); (3) memory (repeated exposures to an antigen will elicit more vigorous immune responses); (4) specialization (optimizing immune responses against different antigens); (5) self-limitation (ability to have immune responses decline after responding to an antigen with the immune system returning to a homeostatic state); and (6) nonreactivity to self (the ability to defend against foreign antigens while not harming the host).1

There are two types of adaptive immunity: humoral (antibody-mediated) and cell-mediated. Cellular components of the adaptive immune response include the following: (1) subpopulations of lymphocytes (e.g., B lymphocytes and T lymphocytes), (2) antigen presenting cells (APCs) (e.g., dendritic cells, monocytes, macrophages), and (3) effector cells (e.g., mononuclear phagocytes).1,107

The function of humoral, or antibody-mediated, immunity is to defend the host against extracellular microbes and other antigens. B lymphocytes (lymphocytes that originate in stem cells and mature in the bone marrow) are the mediators of humoral immune responses. Their primary function is the interruption of infection and the elimination of extracellular microbes. B lymphocytes secrete antibodies (immunoglobulins) that target specific foreign antigens for elimination. There are two types of antibody responses—primary and secondary. A primary antibody response involves the activation, proliferation, and differentiation of naive B lymphocytes into either antibody-secreting cells or memory cells. Some antibody-secreting cells may migrate to, and remain inactive in, the bone marrow. A secondary antibody response involves memory B lymphocytes that are activated to produce increasing amounts of antibodies. Often secondary antibody responses require B-lymphocyte stimulation by helper T lymphocytes. Typically, B cells are capable of producing antibodies to a specific antigen within 5 to 10 days after the initial exposure. With repeated exposures, immunologic memory allows B cells to respond to a specific antigen and produce antibodies sooner (i.e., within 1 to 3 days) with a more intense peak response.1

Cell-mediated immunity is responsible for the destruction of intracellular microbes and is mediated by T lymphocytes (lymphocytes that originate in stem cells in the bone marrow but mature in the thymus gland). The following steps are involved in this process: (1) presentation of a portion of a foreign antigen by major histocompatibility glycoprotein complexes (MHC-I or MHC-II) on the surface of APCs or B cells; (2) cell-associated antigen recognition by naive T cells (i.e., T cells whose function is to recognize microbial antigens); (3) activation of T cells to produce cytokines (e.g., interleukin [IL]-2) and express receptors for the cytokines; (4) T-cell proliferation and clonal expansion (i.e., a rapid increase in antigen-specific lymphocytes); (5) differentiation of the naive T cells into effector cells (whose function is to eliminate the microbe) or memory cells (whose function is to circulate in an inactive state until there is a repeat exposure to the microbe); and (6) inhibition of immune responses by suppressor or regulatory T cells when control or elimination of the foreign antigen has been accomplished.1

Subsets of T lymphocytes have different functions. TCD8+ cells, also called cytotoxic/killer T cells, bind to MHC-I/antigen complexes (see Figure 13-4). All cells have MHC-I molecules that bind and present fragments of intracellular antigens on the cell surface. MHC antigens on the surfaces of cells classify the specific antigenic characteristics of that cell type. MHC-I molecules, present on most cells, can have three different types of MHC-I molecules: HLA-A, HLA-B, and HLA-C. MHC-II molecules, which are found on macrophages and B-cells, have HLA-D/DR proteins. The TCD8+ binds to the MHC-I/antigen complex and then secretes molecules that lyse the infected target cell.1

TCD4+ cells, also called T helper cells, bind to MHC-II molecules, which are found on the surface of antigen presenting cells (APCs) such as macrophages. After binding to the APC, the TCD4+ cell further differentiates into either a T helper (Th) 1 or Th2 cell. Th1 cells release lymphokines, tumor necrosis factor (TNF)-β, interferon (IFN)-γ, interleukin-2 (IL-2) and other interleukins, which facilitate cell-mediated immunity and initiate inflammation. Th2 cells secrete interleukins (IL-4, IL-5, IL-10, IL-13) that facilitate humoral immunity.1,31,127

Although most TCD4+ cells belong to either Th1 or Th2 subsets, approximately 5% to 10% are T-regulatory cells. T-regulatory cells, also called TCD4+/CD25+ or suppressor cells, secrete lymphokines (e.g., IL-10) that are immunosuppressants and inhibit the function of NK cells, Th1 cells, and Th2 cells. These regulatory cells play a role in inhibiting the immune response in the placenta at the fetal-maternal interface.10

In order for an adaptive immune response to antigens to occur, a process called costimulation must take place. Costimulation facilitates the identification of foreign or harmful antigens without jeopardizing the host’s cells and tissues (see Figure 13-2). This process requires that two different signals be recognized by T lymphocytes in order for an adaptive immune response to occur. The “first signal” is the antigen binding to receptors on cell surfaces. For T lymphocytes, this process involves the binding of class I or class II MHC on the surface of an APC to T-cell receptors. The “second signal” involves costimulators that are expressed on APCs. Without costimulation, T lymphocytes are not able to respond to the antigen and they will remain in a state of unresponsiveness or experience apoptosis (i.e., cell death).123

Table 13-2

Definitions of Terms

Active immunity: The response produced by an immunocompetent individual following exposure to foreign antigens (bacteria, viruses, attenuated or inactivated/killed viruses).

Adaptive immunity: Also known as “acquired immunity.” The result of active immunity wherein specific antibody (humoral) and cell-mediated responses establish memory cells and antibodies that provide immunity during subsequent exposures to a specific antigen.

Allograft: Graft taken from an organism that is the same species as the recipient but not genetically identical. The fetus is a “semi-allograft.”

Antibody: Proteins (immunoglobulins) that react with specific antigens. The five classes are IgA, IgD, IgE, IgG, and IgM.

Antibody (humoral)-mediated immunity: Adaptive immune mechanism mediated by B cells, which produces antibodies and protects the body from extracellular antigens.

Antigen: Substances perceived by one’s host defense mechanisms as “foreign” (may include bacteria, viruses, pollutants, dust, certain foods, for example).

Antigen presenting cell (APC): A cell that displays MHC with antigen complexes on the surface of the cell. Any cell can be an APC in that all cells have class I MHC. The term APC is used to refer to cells that also express class II MHC and can activate T cells, dendritic cells, macrophages, and B cells.

Cell-mediated immunity: Adaptive immune mechanism provided by immune cells. TCD4+ (T-helper cells), TCD8+ (T-cytotoxic cells), and TCD4+/CD26+ (T-regulatory cells) provide protection against certain organisms, regulate B-cell function, defend against cancer, and mediate graft rejection.

Chemotaxis: Movement of neutrophils and other phagocytes in an organized fashion toward a site of antigenic invasion.

Complement: Thirty discrete plasma proteins that, as part of the innate immune response, function in a cascade of reactions to form a membrane attack complex that lyses cells. The effector response of the complement cascade also opsonizes antigen, increases vascular permeability, and stimulates chemotaxis to aid phagocytosis. The complement cascade can proceed via the classical pathway or alternate pathway.

Cytokines: Glycoproteins such as lymphokines, interleukins, interferon, and tissue necrosis factor that are produced by various components of the immune system, especially T lymphocytes and macrophages. Cytokines function as autocrine or paracrine agents to activate different arms of the immune response.

Cytotoxic/killer T cell (TCD81): A type of T lymphocyte that acts directly on specific antigens or target cells that exhibit a specific antigen and induces cell lysis.

Fibronectin: Nonspecific opsonin, inhibitor of bacterial adherence to epithelial cells, and clot-stabilizing protein found in plasma and endothelial tissue.

Human leukocyte antigen (HLA): The major forms of specific tissue antigens found on tissue surfaces that are unique to each person (includes HLA-A, HLA-B, HLA-C, HLA-D, and in the placenta HLA-G).

Histocompatibility: The ability of tissue to accept a transplant from another individual.

Immunoglobulin: Antibodies produced by B lymphocytes (IgG, IgM, IgA, IgD, and IgE).

Innate immunity: Initial physical and nonspecific responses. Includes skin, mucosa, digestive enzymes. Primary effectors are polymorphonuclear neutrophils (PMNs), macrophages, monocytes, mast cells, natural killer (NK) cells, and complement. Innate immune response results in elimination of foreign substance or antigen and stimulation of the adaptive immune response.

Interleukin: A polypeptide member of the cytokine family. Produced by T cells, APCs, NK cells, and macrophages. Interleukins regulate and facilitate immune responses.

Interferon: Glycoprotein in the cytokine family. Primary role is in fighting viral infections.

Lymphokine: Subclass of cytokines. Mediators released by activated T cells that facilitate or act as costimulatory for immune reaction.

Memory cell: Form of B lymphocyte sensitized to specific antigens that has the ability to produce specific antibodies with subsequent stimulation by the specific antigen.

Major histocompatibility complex (MHC): Specific antigens found on tissue surfaces divided into two groups: MHC I (HLA-A, HLA-B, and HLA-C, which are found on most of a person’s cells), and MHC II (found on surface of immune cells such as T and B lymphocytes).

Natural killer (NK) cells: A subpopulation of lymphocytes in the innate immune response that form a first line of defense against cells infected with a virus and cancerous cells. NK cells have receptors that recognize class I MHC antigens and can attack without prior sensitization. They secrete cytokines that provide costimulation for T and B cells.

Opsonization: Processing and marking or altering the cell surface of an antigen by actions of immunoglobulin or complement; substances acting in this manner are called opsonins. This process is critical in allowing phagocytosis of organisms with capsular polysaccharide coats such as group B streptococci.

Passive immunity: Transfer of antibodies from an actively immunized to a nonimmunized person.

Plasma cell: Form of B lymphocyte able to secrete immunoglobulins.

Regulatory T cell: TCD4+/CD25+ cells. The exact function of these cells in unclear. They may inhibit production of interleukins (IL-10) that are necessary products and facilitators of the adaptive immune response. Thus they may help to slow or terminate immune response once the antigens are destroyed.

T helper cell (TCD41): A type of T lymphocyte that proliferates when in contact with an APC that exhibits class II MHC/antigen complexes (B cells, dendritic cells). TCD4+ cells differentiate into Th1 or Th2 cells based on the cytokines produced. Th1 cells participate in cell-mediated immunity and Th2 cells participate in antibody-mediated immunity. These cells thus enhance the activity of B lymphocytes, other T cells, and macrophages via secretion of cytokines.

T suppressor cells: T lymphocytes that express CD8+ cells and function to suppress the cellular immune response.

Th1 cells: A subset of TCD4+ (T-helper cells) that facilitates cell-mediated immunity via secretion of interleukin-12 (IL-12), tumor-necrosis factor (TNF)-β, and interferon (IFN)-γ. The result is stimulation of macrophages and inflammation.

 

Toll-like receptors (TLRs): Molecules on the surface of phagocytes and other cells that recognize the patterns of microbial products and generate signals to activate an innate immune response.

Table 13-3

Cytokines: Interleukins and Interferons

CYTOKINE PRINCIPAL SOURCE ROLE IN INNATE IMMUNE RESPONSE ROLE IN CELL-MEDIATED IMMUNE RESPONSE (Th1) ROLE IN ANTIBODY-MEDIATED RESPONSE (Th2)
INTERLEUKIN (IL)
IL-1 Macrophages and other antigen presenting cells (APCs) Costimulation of APCs and T cells, production of prostaglandin, inflammation, acute phase response, hematopoiesis    
IL-2 Activated Th1 cells, NK cells   Proliferations of activated T cells, NK functions Proliferation of B cells
IL-3 Activated T cells     Growth of hematopoietic progenitor cells
IL-4 Th2 and mast cells Monokine production   B-cell proliferation, eosinophil and mast cell growth and function, IgE and class II MHC expression on B cells, inhibition of monocyte production
IL-5 Th2 and mast cells     Eosinophil growth and function
IL-6 Activated Th2 cells, APCs, other somatic cells Acute phase response Synergistic with IL-1 and TNF on T cells, thrombopoiesis B-cell proliferation and differentiation into plasma cells and antibody production
IL-7 Thymic and marrow stromal cells T and B lymphopoiesis    
IL-8 Macrophages, other somatic cells Chemoattractant for neutrophils and T cells    
IL-9 T cells Hematopoietic and thymopoietic effects    
IL-10 Activated Th2 cells, CD8+ T and B cells, macrophages   Suppresses cellular immunity, mast cell growth Inhibits cytokine production, promotes B-cell proliferation and antibody production
IL-11 Stromal cells Synergistic hematopoietic and thrombopoietic effects    
IL-12 B cells, macrophages   Proliferation of NK cells, INF-γ production  
IL-13 Th2 cells     Similar to IL-4, promotes development of eosinophils
INTERFERON (IFN)
IFN-α and IFN-β Mononuclear phagocytes   Antiviral effects, induction of class I MHC on all somatic cells, activation of NK cells and macrophages  
IFN-γ Activated Th1 and NK cells Induces class I MHC on all somatic cells, induces class II MHC on APCs and somatic cells, activates macrophages, neutrophils, NK cells, promotes cell-mediated immunity, antiviral effects    

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Modified from Silver, R.M., Peltier, M.R., & Branch, D.W. (2004). The immunology of pregnancy. In R.K. Creasy, R. Resnik, & J.D. Iams (Eds.), Maternal-fetal medicine: Principles and practice (5th ed.). Philadelphia: Saunders.

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FIGURE 13-1 Summary of innate immunity. Surface antigens of viruses, bacteria, and tumors induce innate immune function. In this system, natural killer cells and phagocytes (e.g., macrophages) can recognize certain antigens in a nonspecific fashion and either lyse the offending infected cells or ingest and destroy the offending organism. Only the foreign nature of the antigen is required; antigen processing and major histocompatibility antigen participation are not necessary. (From Silver, R.M., Peltier, M.R., & Branch, D.W. [2004]. The immunology of pregnancy. In R.K. Creasy & R. Resnik [Eds.], Maternal-fetal medicine: Principles and practice [5th ed.]. Philadelphia: Saunders.)
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FIGURE 13-2 Summary of adaptive immunity. Adaptive immune responses initially require antigen processing and subsequent presentation in T cells. A T cell with a receptor specific for an inciting antigen will be activated and undergo differentiation into a Th1 or Th2 effector cell. In part, the type of cytokine produced by the activated T cell dictates the nature of the subsequent response. Interleukin (IL)-2 is the primary growth factor required for clonal proliferation of T cells; it stimulates the proliferation of cytotoxic and memory T cells. IL-4 and IL-5 stimulate B-cell proliferation, differentiation, and antibody production. (From Sacks, G., Sargent, I., & Redman, C. [1999]. An innate view of human pregnancy. Immunol Today, 20, 114.)

Maternal physiologic adaptations

A general enhancement of innate immunity and suppression of adaptive immunity occur during pregnancy. Within adaptive responses, the cell-mediated (T helper 1, or Th1) response is less functional, the antibody-mediated (T helper 2, or Th2) response is enhanced, and the relation between the two is dysregulated. These alterations, which help prevent the mother’s immune system from rejecting the semiallogenic fetus, increase her risk of developing certain infections and influence the course of chronic disorders such as autoimmune diseases. Because changes in both innate and adaptive immune responses occur, there is no overall trend toward immunosuppression or improved immune function in pregnant women and in general, immune function in pregnant women is similar to immune function in nonpregnant women.

Antepartum period

“Pregnancy is an immunological balancing act in which the mother’s immune system has to remain tolerant of potential major histocompatibility (MHC) antigens and yet maintain normal immune competence for defense against microorganisms.”167 The immune changes that occur systemically in the innate and adaptive systems and those that occur at the site of the fetal-maternal interface are described in this section.

Alterations in innate immunity

Mediators of the innate response are altered during pregnancy (Table 13-4). Chemotaxis (see the definition in Table 13-2) is decreased during pregnancy, which may delay initial maternal responses to infection.48,107 In addition, production of interleukin (IL)-4 and interferon-γ (IFN-γ) may also be decreased.107 Functionally, monocyte and granulocyte activity is enhanced, which results in faster and more efficient phagocytosis. This may help protect the mother so she does not mount a cell-mediated immune response to trophoblastic and fetal cells that appear in the maternal circulation. Natural killer (NK) cell activity is altered in a more complex manner. Systemic NK activity is down-regulated during pregnancy, secondary to the effects of progesterone, which appears to induce formation of a blocking factor that decreases lymphocyte proliferation and NK activity.39 The result is that systemic NK cytolytic activity is normal in the first trimester but lower during the second and third trimesters and immediately after delivery.

Table 13-4

Alterations in Host Defense Mechanisms during Pregnancy

ALTERATION RESULT IMPLICATION
INNATE IMMUNITY    
Increased PMNs Increased available phagocytes Protection of mother and fetus from infection
Altered metabolic activity and chemotaxis of PMNs Delayed initial response to infection, especially gram-negative organisms Increased risk of colonization, urinary tract infection
Decreased NK cell killer activity Delayed initial response to infection

Increased fibronectin Enhanced opsonization Augmented maternal responses against bacterial infection Increased total complement and C2, C3, and C3 split products Enhanced chemotaxis and action of immunoglobulins through opsonization

Decreased C1, C1a, B, and D Delayed initial activation of complement system Protect fetus and trophoblast from rejection ADAPTIVE IMMUNITY Reduction in Th1 responses and inflammatory cytokine production Reduction in cell-mediated responses and graft rejection

Enhanced Th2 response and production of antiinflammatory cytokines Protects mother against infection Reduction in blood levels of immunoglobulins (IgG) in second half of pregnancy PLACENTA AND MEMBRANES Alterations in expression of class I and class II HLA antigens Protects fetus from maternal immune response and rejection Production of IDO IDO catalyzes the degradation of tryptophan, which is essential for T-cell proliferation Protects fetus from maternal immune response and rejection Progesterone Protects fetus from maternal immune response and rejection   Alters NK cells to suppress killer activity   Complement regulatory molecules CD46, CD55 and CD59 Inhibits specific steps within the complement cascade Protects fetus from maternal immune response and rejection

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HLA, Human leukocyte antigen; IDO, indolamine 2,3 dehydrogenase; NK, natural killer cell; PIBF, progesterone-induced blocking factor; PMN, polymorphonuclear neutrophils; Th1, T helper 1; Th2, T helper 2.

Total white blood cell (WBC) volume increases slightly beginning in the second month and levels off during the second and third trimesters. The total WBC count in pregnancy varies among individual women, ranging from 5000 to 12,000 per mm3, with values as high as 15,000 per mm3 reported (see Chapter 8).129 The increase is primarily due to increased numbers of polymorphonuclear neutrophils (PMNs), monocytes, and granulocytes.129 A slight shift to the left may occur, with occasional myelocytes and metamyelocytes seen on the peripheral smear. Changes in other WBC forms are minimal (see Chapter 8).

Alterations in PMN function have been reported.48 PMN attachment, ingestion, and digestion of Candida albicans have been found to be increased, possibly secondary to the effects of human chorionic gonadotropin (hCG). Even so, pregnant women have higher rates of fungal infection, which may be secondary to the effects of estrogen on nutrient availability for fungal growth in the reproductive tract.129 Estrogens may alter local mucosal barrier function, allowing adherence of pathogenic organisms and increasing the risk of colonization. Conversely, improved PMN antibody expression during pregnancy may enhance phagocyte recognition and destruction of antigen-antibody complexes.

Toll-like receptors (TLR) are essential for the innate recognition of microorganisms and endogenous signals from tissue breakdown products, such as fetal fibronectin, hyaluronan, matrix proteins, and biglycans.31 Both TLRs and the recently identified Nod-like receptors (NLR) are thought to be involved in regulating innate responses of the trophoblast to infections and tissue damage signals.4 Changes in the cervix and fetal membranes with tissue remodeling near parturition may release these endogenous signals as part of the cascade leading to labor onset (Chapter 4).31

Alterations in the inflammatory response

Throughout pregnancy, the maternal circulation is seeded with small particles from the trophoblast. These cell clusters function as antigens of fetal origin and stimulate a systemic inflammatory response. The point of direct maternal contact with the placenta is at the junction with maternal endothelial cells in the uterine spiral arteries (see Chapter 3).132 This contact activates endothelial cells and initiates an inflammatory response. However, a glycoprotein known as pregnancy zone protein (PZP) is produced during pregnancy, which has an inhibitory effect on the inflammatory process.150 PZP levels increase 100- to 200-fold during pregnancy. PZP inhibits phagocytosis and suppresses inflammatory responses and IL-2 function near the decidua-trophoblast interface.150,157

Alterations in the complement system

The complement system has a role in both innate and adaptive responses. Although pregnancy stimulates an overall activation of the complement system, this activation does not result in rejection of the fetus.134 Alterations in the function of the complement system during pregnancy begin at 11 weeks’ gestation with an increase (due to greater hepatic synthesis) in both total serum complement and specific proteins of the complement system, including C2, C3, and C3 split products (Figure 13-3).92,134 These components enhance chemotaxis and actions of immunoglobulins through opsonization, thereby augmenting maternal defenses against bacterial infection. Other protein fragments of the complement system, such as C1, C1a, B, and D, are decreased.134 C1q (involved in activation of the classic complement pathway, immune cell modification, cell processes, and maintenance of immune tolerance) is synthesized and secreted by decidual epithelial cells during pregnancy and is thought to have a role in changes in decidual blood vessels and mediation of cell-to-cell interaction between decidual and trophoblast cells.115 Because complement fragments are involved in activation of the complement system, through either the classic or the alternative pathway, activity of the complement system early in the immune response may be delayed during pregnancy.

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FIGURE 13-3 The complement system. The complement system involves a sequential series of discrete plasma proteins and their fragments that, when activated, enhance other parts of the immune system. Actions of complement include attraction of various cell types to the initial site of antigen invasion, promotion of chemotaxis and phagocytosis, enhancement of opsonization and other immunoglobulin functions, enhancement of histamine release and the inflammatory response, and direct destruction of antigens. Proteins of the complement system circulate in the plasma in an inactive state. Complement is activated through a sequential cascade. Activated molecules either act as enzymes to activate other proteins or fragments in the complement system or enhance actions of other parts of the immune system. There are two activation sequences. The classical pathway requires antibody or antigen-antibody complexes for activation, which occurs by C1 through C3. Complement activation and fixation are important for IgG and IgM function. Early in the immune response and during the initial inflammatory response, antibody may not be present, so an alternative activation sequence is needed. The alternative, or properdin, pathway is activated by factors B through C3 by substances such as bacterial products and circulating proteins. (From McLean, R.H. & Winkelstein, J.A. [1984]. Genetically determined variations in complement synthesis: Relationship to disease. J Pediatr, 105, 179.)

Alterations in adaptive immunity

Pregnancy is characterized by a switch in the balance of Th1 and Th2 cell subsets that results in enhanced Th2 function. This change is probably mediated by progesterone, which stimulates production of Th2 cytokines (e.g., IL-3, IL-4, IL-6, IL-10) and reduces the number of Th1 cytokines (e.g., IL-2, IFN-γ, tumor necrotic factor-β [TNF-β]) (see Table 13-3).31,47 Because Th2 responses tend to enhance antibody-mediated responses and Th1 responses enhance cell-mediated immunity (Figure 13-4), this change alters the function of both antibody-mediated and cell-mediated responses. This has a potentially protective role in the maternal-fetal immune relationship.31 Decreases in the number of Th1 cytokines may decrease maternal resistance to the spread of bacterial and viral organisms.31,48 If there are alterations in this pattern so that Th1 predominates during pregnancy, inflammatory cytokine production increases, and is associated with spontaneous abortion, preeclampsia, preterm labor, and fetal growth restriction.31,138 Alterations in adaptive immunity during pregnancy are summarized in Table 13-4.

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FIGURE 13-4 T-cell development from naive T cells to memory T cells. Cytokines released from different T-cell types are indicated as follows: IL, interleukin; IFN, interferon; TNF, tumor necrosis factor. (From Saito, S. [2000]. Cytokine network at the feto-maternal interface. J Reprod Immunol, 47, 92.)

Alterations in cell-mediated immunity.

Cell-mediated immunity is somewhat suppressed during pregnancy. Lymphocyte and macrophage synthesis, activation, and function are altered slightly in pregnancy secondary to influences from estrogens, corticosteroids, progesterone, α-fetoprotein (AFP), hCG, human placental lactogen (hPL), prostaglandins, and serum proteins.47 Corticosteroids suppress activation of T-cell lymphokines, phagocytic activity, and lymphokine responsiveness of the macrophages.47 Prostaglandins (especially PGE1 and PGE2), hPL, and AFP also appear to have an immunosuppressive role during pregnancy. AFP may induce production of regulatory T lymphocytes (CD4+/CD25+).48

Most investigators report that the total number of lymphocytes does not change significantly during pregnancy.48,168 Some investigators have reported a decrease in the T-helper–to–T-suppressor (CD4+/CD8+) ratio. However, most reports indicate that the number of TCD4+ (T-helper cells) decrease progressively to term, while the number of T-suppressor cells (TCD8+) tend to remain relatively unchanged.48

Because TCD4+ cells normally augment the cytotoxic responses involved in graft rejection, a decreased number of these cells may help protect the fetus from rejection by the mother. T-suppressor cell function may increase in late pregnancy and suppress B-cell function.107 Decreased T-lymphocyte function and efficiency may increase the risk of viral and mycotic infections.

Alterations in antibody-mediated (humoral) immunity.

Although a decreased response of B lymphocytes to antigen stimulation in late pregnancy and after birth has been reported by some authors and changes in levels of specific immunoglobulins have been documented, the antibody-mediated immune response is not significantly altered during gestation.

While a few studies have reported an increase in the number of B cells during pregnancy, most studies do not support this finding.48 Some investigators have found that levels of maternal IgG fall as gestation progresses, with decreases ranging from 30% to 40% after 28 weeks.48 However, others have found relatively little change. A decrease in IgG has been attributed to hemodilution of pregnancy, enhanced loss of IgG in the urine, and transfer of maternal IgG to the fetus in the last trimester. This relative decrease in IgG, along with alterations in the WBC population, may increase the risk of bacterial colonization with certain pathogens (e.g., streptococci).

Immunoglobulin A (IgA) decreases or remains stable during gestation, immunoglobulin M (IgM) remains stable or may decrease slightly, immunoglobulin E (IgE) undergoes minimal or no change in levels, and immunoglobulin D (IgD) increases until term. The slight decrease in serum IgA may reflect increased levels of IgA found in saliva and other mucosal fluids.48 The specific role of IgD in pregnancy is unknown.

Immune function at the fetal-maternal interface

The fetus is a semiallograft, that is, foreign tissue from the same species but with a different antigenic makeup. Because the fetus has maternal, paternal, and embryonic antigens, major antigenic differences may exist between the fetus and mother, including blood group antigens and tissue antigens such as human leukocyte antigen (HLA). Protection of the fetus from rejection seems to be predominantly a localized uterine response, although there are also systemic responses mediated primarily by endocrine factors.158 Maternal tolerance of the fetal-placental unit has traditionally been believed to be secondary to elaboration of an immune “barrier” between the placenta and maternal tissue.158 However, it is now understood that maternal immune systems are “aware of fetal antigens, that they respond vigorously to the presence of the fetus and that under normal circumstances they are tolerant to these antigens.”124 Thus tolerance of the fetus by the maternal immune system is “an active mechanism whereby fetal tissues are prevented from being recognized as foreign and/or from being rejected by the cells of the maternal immune system.”158 During pregnancy the trophoblast and maternal immune system have a regulatory and supportive interaction that is critical for both pregnancy maintenance and protection against infectious microorganisms.107 Figure 13-5 illustrates interactions between the maternal immune system and the placental trophoblast.

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FIGURE 13-5 Trophoblast-immune interaction. This model summarizes a new perspective on trophoblast immune interaction, in which the placenta and the maternal immune system positively interact for the success of pregnancy. The trophoblast recognizes, through toll-like receptors (TLRs), microorganisms and the cellular components at the implantation site and responds to them with production of cytokines and chemokines. These factors coordinate the migration, differentiation, and function of maternal immune cells. (From Mor, G. & Abrahams, V.M. (2009). The immunology of pregnancy In R.K. Creasy, et al. (Eds.), Creasy & Resnik’s Maternal-fetal medicine: Principles and practice (6th ed.). Philadelphia: Saunders, p. 91.)

Sperm are MHC class I– and II–negative, which usually protects them from recognition as foreign by the maternal immune system, although both sperm and seminal fluid carry other antigens. Seminal fluid also contains immunosuppressors. The woman responds to specific seminal fluid–induced cytokine and chemokine signals to increase immunosuppressive T-regulating (Treg) cells.137,138 Exposure to paternal antigens on sperm and seminal fluid before pregnancy may lead to decreased responsiveness and maternal tolerance to paternal MHC antigens.138,167

How does trophoblast eliminate or evade the immune responses of B-cell and T-cell activation given the general enhanced innate and humoral immune function that is seen in the systemic circulation during pregnancy? Factors that are currently thought to have a role in maternal tolerance of the fetus include trophoblast HLA-G; progesterone, progesterone induced-blocking factor, altered NK cell function, a Th1/Th2 balance that favors Th2 responses; indolamine 2,3 dehydrogenase (IDO) (catalyzes tryptophan in lymphocytes, an amino acid needed for T-cell proliferation and survival); Fas ligand (immune modulating protein that induces apoptosis of maternal lymphocytes that are fetal antigen reactive); suppressor macrophages; annexin II; lowered complement activity; toll-like receptor (TLR) expression and function; local immune suppression (mediated by Fas/Fas ligand system), and possibly other mechanisms that hide trophoblastic antigens from the maternal immune system.2,39,50,107,142,158

Implantation, the first point of interaction between maternal and fetal tissues, involves an inflammatory process with cross-talk (molecular dialogues) between the decidua and conceptus that increases activity of innate immune cells and is mediated by hormones, growth factors, cytokines, chemokines, adhesion molecules, extracellular matrix components and matrix metalloproteins.51 The inflammatory process at the maternal-placental interface is most marked in the first and third trimesters. In the first trimester these changes occur with the initial contact between the embryonic trophoblast and maternal tissues with implantation and the remodeling of maternal blood vessels.107 In the third trimester inflammation is a critical component of cervical changes in preparation for parturition and labor onset (see Chapter 4).107

After the placenta is established, the two points of contact between maternal and fetal tissues are the syncytiotrophoblast and the extravillous trophoblast. The syncytiotrophoblast is in contact with the endothelial cells of maternal spiral arteries and with the intervillous spaces, and is in direct contact with maternal blood. The extravillous trophoblast (primarily cytotrophoblast) forms the anchoring villi, which are in direct contact with maternal decidual tissue, and remodels maternal spiral arteries (see Chapter 3). Beginning in early pregnancy, small quantities of trophoblast cells detach and enter maternal blood through the uterine veins. These cells form minute emboli that eventually lodge in pulmonary capillaries and are cleared by proteolysis. This appears to be a normal process that does not lead to a maternal inflammatory response or other respiratory distress in women experiencing a normal pregnancy.

Trophoblast and major histocompatibility antigens.

The syncytiotrophoblast does not express either class I or class II MHC antigens, which are the main T cell targets in transplantation rejection.124 The cytotrophoblast has a unique nonclassical MHC-I surface antigen, HLA-G, which does not stimulate the classic cytotoxic T-cell response.85 HLA-G has a Fas/Fas ligand pathway for killing activated T cells and may help prevent maternal rejection of the fetus by inducing apoptosis of activated maternal T cells.32,85 HLA-G inhibits NK cell cytotoxicity and dendritic cell (an antigen presenting cell) maturation.50,176 HLA-G synthesis may be stimulated by IL-10 from the placenta. Extravillous trophoblast expresses HLA-G, HLA-C, and HLA-E (nonclassical MHC-I molecules that help these cells to evade maternal NK toxicity).111,136,176 HLA-G acts on cells of both the innate and adaptive immune systems and has a major role in reprogramming maternal immune responses at the maternal-fetal interface.136 Soluble HLA-G (sHLA-G) molecules are found in maternal plasma and increase from the first trimester on, peaking in the third trimester.136 Decreased expression of HLA-G on the extravillous trophoblast, seen in women with recurrent abortion and preeclampsia, alters conversion of the spiral arteries (see Chapter 3).136,176 Decreased sHLA-G is found with placental abruption, miscarriage, and preeclampsia.135

Trophoblastic cells (specifically the villous cytotrophoblast and extravillous trophoblast) express TLRs and may be able to initiate an innate immune response in the presence of microorganisms at the site of implantation.2,106 In addition, trophoblastic cells contain IDO, which enzymatically degrades tryptophan, a protein essential for T-cell proliferation, and TNF ligands that induce apoptosis. Together these molecules can kill activated immune cells.158

Natural killer cells.

Two subsets of uterine NK cells are seen: endometrial NK cells, seen during the menstrual cycle, and decidual NK cells, which are seen during pregnancy.124,182 Decidual NK cells are critical for pregnancy maintenance.72 The first direct contact between maternal and fetal tissue occurs 6 to 7 days after conception at the time of implantation. Subsequently, the extravillous trophoblast cells invade the maternal endometrial lining and erode the endothelial tissues that line the maternal spiral arteries (see Chapter 3). NK cells in the pregnant decidua are phenotypically distinct from the NK cells in systemic circulation. Peripheral NK cells express CD56dim, CD16+, and CD160+, a combination of characteristics that allow them to be highly cytotoxic. Conversely, decidual NK cells express CD56bright, CD16−, and CD160−, which allows them to produce cytokines such as IL-8 and IL-10 that are beneficial for trophoblastic invasion.69,72,95,111,131 These NK cells also secrete vascular epithelial growth factor (GF) and placental GF, which are angiogenic factors that promote trophoblast invasion and vascular remodling.111,124 NK cells accumulate at the site of implantation and in the decidua. They recognize HLA-G, HLA-C, and HLA-E on the invading trophoblast and influence production of cytokines and cytolytic factors that facilitate decidualization and control of trophoblast invasion, angiogenesis, and growth.86,95,107,119,176 Galectin-1 (Gal-1) is a carbohydrate binding protein with immunoregulatory functions that is found in high levels in uterine NK cells; Gal-1 is also found on trophoblast cells and may help reduce their cytotoxicity.72,130 Up-regulation of Gal-1 induces differentiation of dendritic cells into a phenotype that dampens Th1 responses and suppresses autoimmune inflammation.115 Trophoblast HLA-G can block receptors on the NK cell that initiate cell lysis. Thus the NK cell is altered to augment those functions that protect the conceptus while the general cytotoxic roles are down-regulated. Figure 13-6 illustrates how HLA-G on the trophoblast may inhibit maternal NK cells and block NK cytotoxicity toward fetal cells. Maternal stress, smoking, infection, and other factors can alter the NK phenotype and increase the risk of pregnancy complications.72

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FIGURE 13-6 Cytokine and endocrine networks at the maternal-fetal interface. (From Saito, S. [2000]. Cytokine network at the feto-maternal interface. J Reprod Immunol, 47, 97.)

Decidual macrophages.

Macrophages cluster at the maternal-fetal interface and near the spiral arteries during trophoblast invasion (see Figure 13-5).3 These macrophages produce IL-10, IDO, PGE2, and other anti inflammatory molecules that trigger alloreactivity by the T cells to further protect the fetus.113,158 Placental growth hormone (see Chapter 19) may also alter the maternal immune system.158 Annexin II, a glycoprotein that binds to phospholipids, is produced by the placenta and may inhibit lymphocyte proliferation and IgG and IgM secretion at the placental site. Macrophages stimulated by Th1 cytokines or bacterial products develop a M1 phenotype and produce nitric oxide and free radicals to defend against microorganisms. Macrophages stimulated by Th2 cytokines develop a, M2 phenotype and have immunosuppressive properties. M2 is the common phenotype of decidual macrophages involved in costimulatory signaling.113

T cells and the TH1/TH2 switch.

Overall, there are more TCD8+ cells than CD4+ cells in the maternal decidua, which causes immunosuppressive activity to predominate.107 Changes in the balance of the different T-helper subsets (Th1 versus Th2) result in strengthening of Th2 (antibody-mediated) responses and cytokines (IL-3, IL-4, IL-5, IL-6, and IL-10) and a reduction in Th1 (cell-mediated and graft rejection) responses and cytokines (IL-2, TNF-α, and IFN-γ). This distribution of cytokines at the maternal-fetal tissue interface (see Figure 13-6) is important in implantation, pregnancy maintenance, and maternal tolerance of the fetus. The Th2-specific cytokines IL-4, IL-5, and IL-10 inhibit inflammation and some macrophage functions, and down-regulate IFN-γ production, whereas the Th1 cytokines are the primary effectors of phagocytosis.39,111,126,158 T-regulatory (Treg) cells (see Box 13-2 on page 446) normally account for 5% to 10% of peripheral CD4+ T cells. These increase two- to threefold during pregnancy beginning prior to implantation, peaking in the second trimester, and decreasing by term (this decrease correlates with the decrease in progesterone).111,127 Decreased Treg cells are seen with spontaneous abortion.111,127 The maternal T cells interact with trophoblast cells to support remodeling of the uterine vasculature by removing apoptotic cells, producing matrix proteases, mediating immunotolerance of the fetus, and protecting the fetus from pathogens.113

Nevertheless, the mother initially creates a weak immune response to the fetus/placenta, as evidenced by production of antibody to paternal MHC antigens, production of specific T cells, and weak cellular sensitivity to paternal and fetal antigens.75 This response usually results in an activation (facilitation) reaction rather than rejection response that is mediated by Th2 helper cells with release of Th2 cytokines, which down-regulate Th1 cytokines such as IL-2, IFN-γ, and TNF-α. As a result, maternal immune responses are down-regulated locally at the maternal-placental interface, but are not significantly affected at the systemic level.39 Failure of Th2 responses to increase or of Th1 responses to decrease is associated with an increased risk of recurrent abortion.25,101

Role of progesterone.

Progesterone promotes production of IL-4 and IL-6, the Th1-to-Th2 switch, and IL-4.31,50,126 Progesterone also stimulates activated lymphocytes and decidual cells to synthesize progesterone-induced blocking factor (PIBF).39,155 PIBF stimulates B-cell production of asymmetric antibodies, which are antibodies that have a mannose-rich oligosaccharide group present on one of the Fab regions. Asymmetric antibodies cannot initiate complement or phagocytosis but they can combine with antigen. The result of this combination is an antigen-antibody complex that is univalent and functions as a “blocking antibody” that prevents further antigen-antibody interaction. PIBF also inhibits the cytotoxicity of NK cells.39,

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