Antibody Classes

Another major part of immunology is immunoglobulin structure and function.  The immunoglobulins share structural features, and structural differences impart different functions in immunity (reference).

All immunoglobulins have two heavy polypeptide chains and two light polypeptide chains.  The heavy chains but not the light chains are glycosylated.  Disulfide bonds link heavy chains together and heavy chains to light chains.  The hinge region linking the heavy chains to the light chains is flexible and confers certain properties to the immunoglobulin.  So-called 'constant'  regions are invariable in amino acid sequence.  Antigen binding specificity occurs in the variable and hypervariable regions.

The light chains are ~25 kDa each while the heavy chains are 50 kDa each.  The amino ends of the heavy chains form the Y-arm while the carboxy terminal forms the stem.  Light chain structure includes a constant beta-sheet domain at the carboxy end, and this region occurs in two types, kappa and lambda.  Each lambda gene has five different versions of the constant region. The variable region features 3 loops that stick out to form the hyper variable region.  The heavy chain in the same area also has 3 hyper variable loops, and the six loops form the CDR or complimentarity-determining regions.

As alluded, the heavy chain structure shows variability in the amino-terminus progressing to a first constant region, then a 'hinge' region.  The hinge region is rich in proline and has one or more disulfide bridges between the two heavy chains.   For the D, G, and A classes, (with corresponding delta, gamma, and alpha heavy chains) there is flexibility.  The M-class and E-class (mu and epsilon heavy chains) forms a rigid bend at C2 between two constant stem domains (C3 and C4).

The carbohydrate attachments occur in the C2 region of the D, G, and A immunoglobulins and in C3 of the M and E classes.  The oligosaccharides are added post-transcriptionally in the stem opens the Fc stem.  The carbohydrates are important for complement interactions.  The attachment is an N-linkage to the glycosyl chain, and in the example below, the oligosaccharide shows 13 sugar residues including GlcNAc (N-acetyl glucosamine), mannose, fucose, galactose, and sialic acid.  There is diversity in the glycosylation.  It seems the glycosylation pattern is important in immunoglobulin interactions with viruses and bacteria.

The carboxy terminus (C3 of the D, G, and A classes and C4 for the M and E classes) determine whether or not the immunoglobulin is secreted or is membrane bound.

• Naive cells and memory cells feature membrane-bound immunoglobulins, the sequences at the terminus being hydrophobic followed by hydrophilic.
• The secreted versions are expressed in plasma cells have a short hydrophilic sequence at the carboxy-terminus.

This basic structure occurs in five classes of antibodies: IgA, IgD, IgE, IgG, and IgM.

IgA: These are the only dimerized class, and there are two types.  They are found in mucosal tissues (e.g., gut, urogenital, and respiratory tract) as well as saliva, tears, and breast milk.  Their main function is thought to be prevention of pathogen colonization.

1. Functions at epithelial barrier to prevent colonization.
   
2. Monomer can be found in serum but,  
   
3. The secreted form occurs as dimer, looking like 2 IgG's stuck together, stems in, 4 antigen-binding sites out, and may occur as trimer or even tetramers
   
4. Two subclasses (1 and 2)
   
5. Also held together by an additional peptide, the J chain (binds secretory peptide) which is identical to the one in IgM
   
6. Secreted into mucus, tears, saliva, and breast milk- up to 15 grams per day!
   
7. Plasma cells that secrete this tend to home in on various epithelial linings.
   
8. Pathogen proteases can inactivate IgA by cleaving at the hinge region
   

IgD: Monomeric in structure like IgG and IgE, this class functions as a B-cell antigen receptor that have not been exposed to antigens.  It activates basophils and mast cells.

1. Function- aids recognition by naïve B cell.
   
2. Primarily found (with IgM) as a membrane-bound receptor in naïve B cells. While
   M class antibodies also function in plasma, D class rarely does.
   
3. Rarely found in plasma (0.2% of total serum immunoglobulins)
   
4. superficially resembles IgG (different amino acid sequence). 
   

IgE: Monomeric in structure, functioning to protect against parasites.  It binds to basophils and mast cells, causing release of histamine.  It is the main immunoglobulin involved in allergies.

1. Function – defense again worm parasites.
   
2. Monomer superficially resembles IgM (somewhat different amino acid sequence)
   
3. rare, but potent
   
4. involved in allergic response
   
5. binds to FC (stem) receptors on mast cells and basophils, which causes them to
   trigger the allergic reaction. 
   

IgG: Monomeric in structure with four forms, these provide the major mechanism of adaptive immunity.  It is the sole class able to cross the plancenta and give passive immunity to the fetus.

1. flexible hinge, 3 constant domains
   
2. standard secreted antibody defending against bacterial and viral pathogens
   
3. comes in four versions, numbered 1 to 4, varying in biological specificity:
   IgG1 – activates complement, Fc receptors bind tightly
   IgG2 – weakly activates complement, Fc receptors bind weakly
   IgG3- strongly activates complement and binds tightly to Fc (lots disulfides) IgG4 – does not activate complement, binds weakly to Fc. 
   

IgM: Is pentameric in structure in secreted form but monomeric when expressed on the B cell surface.  IgM is the first responder to eliminate pathogens before there is sufficient IgG.

1. rigid bend – 4 constant domains
   
2. Function- general purpose - First class expressed in plasma.
   
3. Monomeric form (actually 2H +2L) expressed as a membrane-bound antibody on the naïve B cell.
   
4. Secreted form occurs as pentamer, looking like 5 IgG's stuck together, stems in, 10 antigen-binding sites out.
5. Held together by an additional peptide, the J chain. The J chain binds to a secretory component, a peptide that allows structure to be secreted into mucus, etc. (Figure 4.23)
6. Very good at binding large complex structures and activating complement (to kill foreign cells). 

The subjects of Immunity

The immune system acts against invading viruses and organisms.  The invaders would drain the host of nutrients and energy if not for immunological intervention.  The first lectures assert that modern times allow for generally pathogen-free living mainly by providing clean water and public sanitation (proper sewage disposal).  Also important are vector control (mosquito abatement), food safety, and vaccination.  Pathogens are grouped in different categories beginning with acellular viruses, prokaryotic bacteria, unicellular eukaryotes including fungi, protozoans, and finally multicellular worms platyhelminthes and nematodes.  In addition to availing oneself of modern safeties listed above, the simple act of washing hands frequently can have a large beneficial health result even before considering the immune system.

The different categories of pathogens offer different surface features that allow recognition by the immune system.  These features differ from the surface features of our own cells, thus allowing evolution of a system that distinguishes invader from self.  There are two different classes of recognition in the system: the innate and the adaptive.  Innate recognition involves detecting general patterns of molecules associated with the various pathogen classes and does not require prior exposure.  Adaptive response involves recognition of specific molecules associated with specific strains within the pathogen class.  It is developed after exposure to the pathogen.

After recognition in either category, the system has different levels of responses, ranging from relatively benign to all-out war.  These responses can also be misdirected, such misdirection characterized as allergies, inflammation, and autoimmune disease.

Innate	Fast (minutes)	Always there	Recognizes patterns	Phagocytes, NK cells, proteins & barriers
Adaptive	Slower-weeks initially, 3 or more days subsequently	requires gene rearrangement	Recognizes specific proteins	B and TH and Tc cells

I am unsure about how much augmentation I need on the blog.  I could incorporate all of the notes, but that makes no sense.  Perhaps creating links external to the course will enhance my understanding and 

More Objectives

I know some immunology, so what is it I am hoping to gain in the course?

I know, for example, that the immune system works to rid an organism of foreign invading organisms, including viruses.  The system has many different components, that is, different cell types that have different functions in performing this overall task.  I assume there are different types responsible for different threats.  There are cells and mechanisms involved in clearing viruses that are different from the cells and mechanisms for bacteria, and different ones for unicellular pathogens, and different ones for multicellular parasites.  There is redundancy within the system such that there are rapid responses and more long term remedies.  Immunization is the purposeful introduction of an antigen to elicit a response that is 'remembered' such that when a similar antigen from a real threat is perceived, a rapid response of the system can clear the infection before undesired consequences of infection can occur.

There are cell surface receptors and signals that 'turn on' or up-regulate the system, and others that 'turn down' or down-regulate the system.  Inflammation is one of the more obvious signs of the activated immune response.  Pathogens often have mechanisms that allows the pathogen to be undetected.  What are examples of those mechanisms?  Much is known about the immune system in undesirable function such as autoimmune diseases, sepsis, and cancer.  In autoimmune disease, the immune system attacks self.  What is the mechanism of dysfunction here?  In sepsis, an emergency response of sorts occurs such that the organism undergoes life-threatening temperature and organ failure.  How?  Why?  In cancers, rogue cells that are normally recognized and destroyed by the system are undetected and proliferate.  Why?  Cell and organ transplantation is challenged by immune response rejection.  How is this mediated?

I know about macrophages that engulf foreign matter to destroy it.  The mechanisms of destruction involve oxygen radicals, proteases, nucleases, and other degradative processes, but what are the details?  Apoptosis is a programmed cell death, but how is this process used in the immune system.  Antibodies have structures that bind to foreign antigens and are derived from shuffling variable regions of genes to generate diversity.  Through somatic cell selection, the antibodies with high affinity for the antigen are selected, and the cells proliferate to deliver antigen-binding immunoglobulins important in the immune response.  How is selection achieved?  What happens to the unselected cells?

There are a lot of questions.  Now on to some answers.