Innate Immunıty

3. The Alternative Complement Pathway

Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize a few highly conserved structures present in many different microorganisms. The structures recognized are called pathogen-associated molecular patterns and include LPS from the gram-negative cell wall, peptidoglycan, lipotechoic acids from the gram-positive cell wall, the sugar mannose (common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial DNA, N-formylmethionine found in bacterial proteins, double-stranded RNA from viruses, and glucans from fungal cell walls. Most body defense cells have pattern-recognition receptors for these common pathogen-associated molecular patterns and so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 molecular patterns. All of this will be discussed in greater detail in upcoming pages.

The innate immune responses involve:

• Phagocytic cells (neutrophils, monocytes, and macrophages);

• Cells that release inflammatory mediators (basophils, mast cells, and eosinophils);

• Natural killer cells (NK cells); and

• Molecules such as complement proteins, acute phase proteins, and cytokines.

Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, and fever. In the next several pages we will look at each of these in greater detail.

The complement system refers to a series of proteins circulating in the blood and bathing the fluids surrounding tissues. The proteins circulate in an inactive form, but in response to the recognition of molecular components of microorganism, they become sequentially actived, working in a cascade where in the binding of one protein promotes the binding of the next protein in the cascade.

There are 3 complement pathways that make up the complement system: the classical complement pathway, the lectin pathway, and the alternative complement pathway. The pathways differ in the manner in which they are activated and ultimately produce a key enzyme called C3 convertase:

We will now take a closer look at the alternative complement pathway.

The Alternative Complement Pathway

The alternative complement pathway is mediated by C3b, produced either by the classical or lectin pathways or from C3 hydrolysis by water. (Water can hydrolize C3 and form C3i, a molecule that functions in a manner similar to C3b.) Activation of the alternative complement pathway begins when C3b (or C3i) binds to the cell wall and other surface components of microbes. C3b can also bind to IgG antibodies. Alternative pathway protein Factor B then combines with the cell-bound C3b to form C3bB. Factor Dthen splits the bound Factor B into Bb and Ba, formingC3bBb. A serum protein called properdin then binds to the Bb to form C3bBbP that functions as a C3 convertase capable of enzymatically splitting hundreds of molecules of C3 into C3a and C3b. The alternative complement pathway is now activated.

Some of the C3b subsequently binds to some of the C3bBb to form C3bBb3b, a C5 convertase capable of splitting molecules of C5 into C5a and C5b

The beneficial results are the same as in the classical complement pathway above.

• Trigger inflammation (C5a>C3a>c4a);

• Chemotactically attract phagocytes to the infection site (C5a);

• Promote the attachment of antigens to phagocytes via enhanced attachment or opsonization (C3b>C4b);

• Serves as a second signal for the activation of naive B-lymphocytes (C3d);

• Cause lysis of gram-negative bacteria and human cells displaying foreign epitopes (MAC); and

• Remove harmful immune complexes from the body (C3b>C4b).

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