Bio 328 - Innate ( Nonspecific ) Immunity

Lecture 1 - Innate ( Nonspecific ) Immunity - The term, Innate immunity, refers to the basic resistance to disease that a species possesses - the first line of defense against infection.
The characteristics of the innate immune response include the following:

  • Responses are Broad-Spectrum (non-specific)
  • There is no memory or lasting protective immunity
  • There is a limited repertoire of recognition molecules
  • The responses are phylogenetically ancient

Potential pathogens are encountered routinely, but only rarely cause disease. The vast majority of microorganisms are destroyed within minutes or hours by innate defenses. The acquired specific immune response comes into play only if these innate defenses are breached.

In this lecture we will review the elements of the innate immune response.

Anatomic Barriers

Skin (physical barrier, low pH due to lactic and fatty acids)
epidermis - thin outer layer containing tightly packed epidermal cells and keratin (water-proofing) completely renewed every 15-30 days.
dermis - thicker inner layer contains sebaceous glands associated with hair follicles - produce sebum which consists of lactic and fatty acids maintaining a pH 3-5.

Mucous membranes (ciliated epithelial cells; saliva, tears and mucous secretions) - GI, urogenital, respiratory tracts - collectively represents a huge surface area.

Physiologic Barriers

Temperature - normal body temperature inhibits growth of most microorganisms.

Elevated body temperature (fever) can have a direct effect on pathogenic microorganisms.

pH - low pH of stomach, skin, & vagina (inhibits microbial growth)

Oxygen tension

Huge number of chemical factors (a few examples given below):

  • Fatty acids, lactic acid
  • Pepsin (digestive enzyme which hydrolyzes proteins)
  • Lysozyme -hydrolytic enzyme found in mucous secretions - able to cleave the petidoglycan layer of the bacterial cell wall
  • Anti-microbial substances which directly destroy microorganims: cryptidins and a-defensins (produced in base of crypts of small intestine - damage cell membranes) b-defensins (produced within skin, respiratory tract - also damages cell membranes) surfactant proteins A & D (present in lungs - function as opsonins which enhance the efficiency of phagocytosis)
  • Interferons - group of proteins produced by cells following viral infection. Secreted by the cells, and then binds to nearby cells and induces mechanisms which inhibit viral replication.
  • Complement - a group of serum proteins that circulate in an inactive proenzyme state. These proteins can be activated by a variety of specific and nonspecific immunologic mechanisms that convert the inactive proenzymes into active enzymes.ssss The activated complement components participate in a controlled enzymatic cascade that results in membrane-damaging reactions which destroy pathogenic organisms by formation of a membrane attack comples (MAC).

Endocytic and Phagocytic Barriers Endocytosis - Process by which macromolecules contained within the extracellular tissue fluid are internalized by cells. Internalization occurs as small regions of the plasma membrane invaginate, or fold inward, forming small endocytic vesicles known as endosomes. Occurs through pinocytosis or receptor-mediated endocytosis.

Pinocytosis - nonspecific membrane invagination Receptor-mediated endocytosis - specific, macromolecules are selectively internalized after binding to specific membrane receptors.

Following internalization, the endosomes fuse with primary lysosmes. Lysosomes contain large numbers of degradative enzymes (> 20 different hydrolytic enzymes including proteases, nucleases, lipases, etc). The ingested macromolecules are subsequently digested into small breakdown products. Products not utilized by the cell are released through the process known as exocytosis.

Phagocytosis Involves the ingestion of particulate material including whole pathogenic microorganisms. The plasma membrane expands around the particulate material to form large vesicles called phagosomes (10-20times larger than endosome). Only specialized cells are capable of phagocytosis, whereas endocytosis is carried out by virtually all cells. Once particulate matter is ingested into phagosomes, the phagosomes fuse with lysosomes and the ingested material is then digested by a process similar to that seen in endocytosis.

The so-called "professional phagocytes" include: monocytes & macrophages, neutrophils, and dendritic cells

There are a few other cells which can be induced to become phagocytic under certain circumstances (i.e. during intense inflammation) Both fibroblasts and epithelial cells are known as "non-professional" phagocytes.

How Do Phagocytic Cells Distinguish Between Self/ and Non-Self?

Increasing experimental evidence in this field suggests that organisms recognize invading microorganisms by recognizing common microbial patterns (i.e. molecular patterns). Perhaps surprisingly, it appears that essentially all eukaryotic organisms recognize and respond to the same microbial patterns. This would suggest that these innate mechanisms for self/non-self recognition are phylogenetically ancient.

A partial list of these microbial patterns follows:

  • LPS- lipopolysaccharide (associated with the outer membrane of Gram - bacteria)
  • Mannose, fucose, and other sugar residues (not just absence/presence but also factors like spacing between sugars on the cell surface)
  • Techoid acid (associated with the peptidoglycan cell wall of Gram+ bacteria)
  • N-formyl peptides ( recall that all prokaryotic protein sequences begin with a formyl-methionine)

These common microbial patterns are recognized by host proteins which have been termed Pattern Recognition Molecules (PRMs) or Pattern Recognition Receptors (PRRs).

A partial list of these PRMs follows:

  • f-Met-Leu-Phe receptor (binds to N-formyl peptides, and when present attracts neutrophils)
  • Complement receptors- designated CRs - (binds to complement components such as C3b and C4b which opsonize microorganims as a consequence of the activation of the complement cascade)
  • Macrophage Mannose receptor (binds to mannose residues commonly present on surface of microorganisms)
  • Scavenger Receptors - at least 6 different scavenger receptors with different specificities have been described (recognize certain anionic polymers and acetylated low-density lipoproteins)
  • CD14 (receptor on the surface of phagocytes which allows for the recognition of LPS)

The interaction between a PRM and its microbial pattern leads to a rapid cascade of events. Just to give one example of the nature of these interactions we will take a look at the interaction between CD14 and its ligand: CD14 cannot bind to LPS directly. A protein termed LBP (for lipopolysaccharide binding protein) must first bind to LPS. The LPS-LBP complex then binds to CD14 and the receptor-ligand complex is internalized. In addition, CD14 is associated with a protein known as Toll-like receptor 4 (TLR-4). As a consequence of the CD14-LPB/LPS interaction at the level of the membrane, TLR-4 becomes activated. TLR-4 plays an important role in signal transduction [ transfer of the signal received at the cell membrane eventually to DNA sequences located in the nucleus of the cell]. Importantly, TLR-4 is now known to activate a transcription factor known as NFkB. NFkB activation eventually leads to transcriptional activation resulting in the synthesis of:

  • ROIs (Reactive oxygen intermediates) and RNIs (Reactive nitrogen intermediates) - highly toxic to microorganisms anti-microbial peptides (such as the defensins)
  • Cytokines (the small proteins which function as the chemical messengers of the immune response facilitating cell-cell communication)
  • Chemokines (small proteins which function in the chemotaxis of leucocytes) adhesion molecules (proteins which regulate the adhesive properties of leucocytes leading to alterations in leucocyte migration and trafficking)
  • Acute phase proteins (proteins synthesized largely in the liver and secreted rapidly following infection or tissue injury)

Toll and Toll-Like Receptors Toll receptors were first identified in the fruitfly, Drosophila, and were shown to play a very important role in the development of the insect. More recently, toll receptors have been shown to also be involved in the innate immune response of fruit flies and other insects. A long list of similar proteins have been discovered in a very wide variety of vertebrate organimsms including humans.

Back