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Immunology’s ‘dihybrid cross’ : Antibody response to different antigens

25 Nov

The progress of infection can be summarized as a pathogen going through a series of steps:

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Progress of Infection

The first three steps, ‘Portal of Entry’, through ‘Surviving Host Defences’ encapsulates all of the immune response. Some key events in the immunity are inflammation and the innate  response, antigen processing and presentation, adaptive immunity and memory.

Several of these topics I’ve described here before including an outline of the development of lymphocytes (B and T Cells – sorry NK Cells) in an article here. The activation of B cells here, immunological memory in several places including here.  Some of these topics I have yet to address (e.g. a good discussion of inflammation), and others (e.g. antigen processing and presentation) have been buried in other posts (see my lymphocyte development, B cell Activation or this post on Transmissible tumors). 

This time, I thought I’d prevent a sketch of the humoral immune response and how this illustrates, like Mendel’s traits in a dihybrid cross, that each immune reaction is ‘independent’. A typical immune response is outlined below showing the development of antibodies following a primary response and then a more rapid and robust secondary response. If we want to compare this response to Mendel’s monohybrid cross, we can see the same response for antigen after antigen just as Mendel saw the same pattern of inheritance for any single trait he observed.

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Response to a single antigen

 

Before we had the ability to ‘see’ this response on a molecular level, we could see its effects on people. Those who previously contracted a disease did not contract that same disease a second time. This immunological memory is the basis for vaccination, where we separate the disease-causing agent from the immunological memory-inducing agent for any given pathogen and then use only the later to vaccinate.

However, Mendel continued to examine traits and how they were inherited individually (i.e. the inheritance of one trait had no bearing on the inheritance of another). He called this independent assortment. Is there a similar experiment that can be done to show ‘independent immunity’?

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Response to two antigens independently

Borrowing a figure from Abul Abbas’ text on Cellular and Molecular Immunology, we see  that the response to one antigen has no bearing on the body’s response to a second, unique antigen. Like Mendel’s dihybrid crosses, the response to two antigens is, indeed, independent. (Note, the serum titer in this graph falls much lower than that in the first illustration – this second curve is more representative for real responses. Regardless, the antibody titer for a secondary response remains higher than that of the primary response.)

The primary response to antigen B is identical to the primary response to antigen A. The secondary response to antigen A results in a more rapid, robust response and eventually levels out to a higher steady-state of serum antibody.

To extend the analogy just a bit further, one might ask if there is such a thing in immunology that parallels the ‘linked genes’ of inheritance?

In fact, there is. The world’s first vaccine, developed by Edward Jenner in 1796, involved the use of cowpox pus to induce protective immunity to both cowpox and the related virus, smallpox. This seems to violate our rule of independent immunity, just as the Morgan lab found that genes for body color and wing formation were found to be inherited together in fruit flies, thus violating the Law of Independent Assortment (of alleles).

In the case of cowpox and smallpox, this comes from the similarity in antigens made by each of these viruses. That is, the cowpox antigens the body generates an immune response against are NOT (ENTIRELY) UNIQUE from antigens found in smallpox. When the vaccinated individual is challenged with smallpox, antibodies created to defend against a secondary challenge with cowpox react to the smallpox antigens as if this was a secondary response directed against smallpox.

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Primary reaction to Cowpox antigen (A) is used for vaccination. Secondary reaction to Smallpox antigen (A’) upon challenge.

 
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Posted by on November 25, 2013 in Uncategorized

 

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A quick description of Lymphocyte Development and Activation

25 Apr

Lymphocytes Development and Activation

Lymphocytes (B cells and T cells – we’ll not talk about NK cells here) go through a generalizable sequence of maturation events. Each starts in the Bone Marrow (BM) as a Hematopoietic Stem Cell (HSC), where it starts its development. T cells leave the BM relatively sooner and go to the Thymus, while B cells remain in the BM for most of their development and then finalize development in the spleen.

 Positive Selection for BCR/TCR Development

Regardless of the type of cell (T or B), development occurs in two stages – First, each cell will attempt to make a unique lymphoid receptor (B cells have a BCR; T cells have a TCR). In order to do this, genetic material must be shuffled. While this shuffling does randomize the binding pocket of the lymphoid receptor, it may also destabilize these same receptors’ structure. To account for this, lymphocytes undergo a ‘positive selection’ period that ensures that a viable receptor is formed. This is actually done twice: once to ensure that a ‘Pre-Lymphoid Receptor’ is formed and again to for a ‘Mature Receptor.’  However, both are considered positive selection. Failure to pass this selection point leads to death of the cell. (In the figure below, Pre-Lymphocyte receptors are colored red, mature receptors are grey)

Negative Selection Against Self-Reactive BCR/ TCRs

Once cells have survived positive selection, they are considered Immature Lymphocytes. Although the terminology is poor here, these immature cells have mature lymphocyte receptors. At this point, these receptors have to be tested against all possible ‘Self ‘- antigens. In this case, binding means that these cells have the potential to react against the self – this is a no, no. The Immune System turned against the self is extraordinarily dangerous. Therefore, self-reactive cells are eliminated during this negative selection process. (In the figure below, mature lymphocytes have grey nucleus, all prior stages have red nuclei).

LymphosFollowing these developmental stages, the cells that have survived both positive and negative selection are 1) stable, mature lymphocyte receptors and 2) not reactive to ‘self’. These cells then enter the immune repertoire for that organism and are available to react against any foreign threats. Again, it is important to emphasize that each lymphocyte has a unique receptor and therefore will only get activated by a unique foreign antigen.

I may write more later to discuss some of the details that distinguish B and T cell development, but for now, this generalizable description will suffice.

Clonal Selection

Once a part of the immune repertoire, lymphocytes are on the lookout for foreign antigen that is capable of being bound by that cell’s receptor. Depending on the cell type, this interaction may be in one of several contexts (either in the context of MHC I, MHC II or as a naïve, soluble antigen), but regardless of the context, these ‘naïve’ lymphocytes will become activated by binding of their lymphocyte receptor. And once activated, lymphocytes will proliferate and differentiate. Differentiation typically goes in one of two general directions:

1)   generating activated effector cells (these secrete antibody if B cells, kill target cells, if CD8 T cells, or become helpers if CD4 T cells)

–or-

2)   generating memory cells, cells that act the same as the mature naïve cell that was activated, but are more numerous and can, themselves be activated upon stimulation.

An example of this activation is shown below in this HHMI video about how CD8 T cells can be stimulated to activate and then kill any target cells. This video also does a good job of illustrating how antigens get digested within a cell and expressed in the context of MHC I.

http://www.hhmi.org/biointeractive/media/antigen_ctl-lg.mov

 
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Posted by on April 25, 2013 in Uncategorized

 

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Complement – an antibody-guided innate immune response

11 Apr

That’s a complicated title. What it means is that complement is part of out innate immune response, i.e. it is pre-made, ready-to-go and does not adapt over time in response to immune challenges. However, it is guided by antibodies, which are part of the adaptive immune response.

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This bad guy, invading cell, has been opsonized by antibodies – they bind all over the cell 1)preventing it from binding other host cells and 2)recruiting complement and immune cells.

What complement is, is a number of proteins that come together and activate one another in a cascade that coordinates the formation of a hole- or pore- through the membrane of foreign cells. The cascade begins when the first of the complement proteins associates with antibodies that are opsonizing a foreign cell.

Once recruited, complement proteins will activate in a cascade (see movie) in which small parts of the proteins break off and act as anaphylatoxins recruiting and activating  immune cells to the region. Meanwhile, the larger protein elements will assemble into pore-forming complexes that will kill the invading cell.

With this in mind, watch the animation below looking for:

1) antibodies binding to foreign cells

2) early complement proteins being recruited

3) complement breaking into large and small proteins

4) the smaller ones floating away to recruit immune cells

5) the larger ones forming membrane pores and killing the invading cell.

(don’t worry about the sequence of events or the specific proteins involved)

 
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Posted by on April 11, 2013 in Uncategorized

 

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