Gerald W. Volcheck - Clinical Allergy: Diagnosis and Management

Division of Allergic Diseases, Mayo Clinic Rochester, College of Medicine, Mayo Clinic, MN

APC

BCR

COX

CpG

FcR

FcRI

GM-CSF

H

HLA

ICAM

IL

IL-1Ra

IL-2R

IFN

LFA

LPB

LPS

LT

MBL

MBP

MHC

NK

PAMP

PG

PLA

SCF

TCR

TGF

TLR

TNF

TXA

VCAM

The immune system is a vast network that involves many interacting constituents. This chapter provides an overview of the immune system to establish a sense of the communication and checks and balances between the cells and mediators that provide immune protection and the process that occurs in allergic or hypersensitivity responses.

The immune response does not occur in a strictly linear pattern. Although allergen exposure activates the allergic immune response, the subsequent immune cell and mediator cascade includes numerous intersecting positive and negative feedback loops. Initially, it is difficult to visualize all the interconnecting pieces of the immune response. The chapter presents the response chronologically, acknowledging that multiple processes occur simultaneously. The chapter begins with the innate immune response because this is the bodys first response to a foreign protein. This is followed by the acquired immune response, which is activated just after the innate immune response. Both of these processes subsequently work together interdependently. Next, the key components of the acquired immune response are reviewed, with the focus on antigen presentation, the major histocompatibility complex (MHC), and T- and B-cell interaction and activation. As knowledge of the immune system has evolved, a major focus has been on cytokines, the secretory proteins that function as mediators of immune and inflammatory reactions. The cytokines, as presented, are grouped by their physiologic activity, which further underscores the intricate communication between the various cell types of the immune system. This emphasizes how the predominance of certain cytokine subsets determines the type of immune response that occurs (cytotoxic, humoral, cell-mediated, or allergic). The chapter ends with an overview of the allergic response, with a focus on how current and experimental immunomodulatory medications may be used to attenuate the allergic response.

The innate immune system represents the hosts first line of defense against pathogens from the environment. Unlike the acquired immune system in which gene elements are rearranged somatically to produce specific antigen-binding molecules, the innate immune system contains responses that are encoded by the genes in the hosts germline. These elements are present from the outset and do not require previous exposure: they are inborn. This system recognizes foreign matter, such as that contained by microbes, that is not present in the host. The innate and acquired immune systems work in concert to fight pathogens. The differences between these two systems are outlined in Table .

The innate immune system contains many components. The first line of the bodys defense against invaders includes physical barriers such as skin (epithelial barriers) and mucous membranes. The three major interfaces between the body and the external environment are the skin, the gastrointestinal tract, and the respiratory tract. The organs of the integumentary, gastrointestinal, and respiratory systems have multiple specialized features that help repel foreign invaders; for example, the lactic acid in sweat maintains an acidic pH that prevents bacterial colonization, and the epithelia lining the respiratory tract contain a flowing layer of mucus that sweeps away foreign substances. In addition, these areas are lined by epithelia that can produce peptide antibiotics to kill bacteria and intraepithelial lymphocytes that likely signal the presence of a pathogen. To cause infection, bacteria, viruses, and parasites must first penetrate these physical barriers. In addition to preventing infection, these physical barriers decrease allergen exposure. Disruption of the epithelial lining and mucous membranes increases allergen exposure, thus resulting in a greater chance of sensitization and a greater allergic response in persons genetically predisposed to the development of allergy.

After the pathogen penetrates the physical barriers, it encounters the second line of defense, namely, the immune cells and proteins of the innate immune system. The innate immune system is manned primarily by macrophages, neutrophils, natural killer (NK) cells, complement, and soluble, bioactive proteins and molecules. The primary function of these cells and proteins is to destroy any invading pathogen. These components and their function in relation to the innate immune response are discussed briefly below.

Macrophages are the primary first-line cells of the innate immune response. They are able to migrate to areas of invasion and phagocytose the pathogen. Macrophages are derived from monocytes. Monocytes are produced in the bone marrow and circulate for approximately 24 hours before settling in the tissue where they become tissue macrophages. Monocytes contain lysosomes and organelles needed to synthesize secretory and membrane proteins. Monocytes, like neutrophils, can be attracted to an area of inflammation through the three-phase endothelial attachment process (described below). The specific chemoattractants differ somewhat for neutrophils and monocytes because these cells have different chemokine and cytokine receptors. Therefore, the chemokines, cytokines, and other mediators released by the immune cells determine whether monocytes, neutrophils, or other leukocytes are attracted to the area of inflammation. This pattern of released mediators attracting different cell types holds throughout the various types of immune reactions. Basically, the body signals for what it needs to fight the pathogen.