Question 2 (4.5 points): A mouse line (called ‘Wm’) is discovered that has an un

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Question 2 (4.5 points): A mouse line (called ‘Wm’) is discovered that has an unexpected immunodeficiency. Genetic studies indicate that the immunodeficiency is due to a single gene defect. Wm mice have normal numbers of all immune cell lineages, including T cell, B cells, macrophages, dendritic cells, NK cells, and granulocytes. Also, when infected with viruses or intracellular bacteria and protozoa, Wm mice mount normal protective T cell responses and clear the infections. However, when given a helminthic parasite infection, Wm mice cannot clear the parasites and die from the infection. A set of wild-type (WT) and Wm mice were infected with the helminthic parasite, Nippostrongylus brasiliensis, and cytokine production by CD4 T cells was analyzed. For this experiment, CD4 T cells were isolated from mice at day 8 post-infection, stimulated in vitrofor 24 hr stimulation with anti-CD3 antibody to elicit cytokine secretion, and then cytokine levels in the culture supernatants were examined by ELISA. The results are shown in Figure 2.A below.

Figure 2.A

a)(1 point) What appears to be the problem in Wm mice? Explain your reasoning.

b) (1.5 points) List three possible candidates for the defect in Wm mice. Note that the transcription factor GATA-3 is nota likely candidate gene, as GATA-3-deficient mice have an early block in T cell development in the thymus, and completely lack all T cells.

To learn more about the defect in Wm mice, naive CD4 T cells were isolated from wild-type and Wm mice and stimulated in vitrowith anti-CD3 plus anti-CD28 antibodies to artificially induce activation. These CD4 T cells were activated either in the presence of additional cytokines, or blocking antibodies, as indicated in the figure. After three days of stimulation, T cells are isolated, washed, and restimulated with anti-CD3 antibody in medium lacking any cytokines or antibodies. After 24 hr, the cytokines present in the supernatants of these re-stimulated CD4 T cells are examined by ELISA. These data are show in Figure 2.B below.

Figure 2.B

c)(2 points) Based on these results, what is a possible explanation for the defect in Wm mice? Explain your reasoning.

IL-4 (ng/ml) IL-5 (ng/ml) IL-13 (ng/ml) IFN-y (ng/ml) Cytokine production 15 Cytokine production Cytokine production 0.3 uction 12 10 0.2 0.1 W-t Wm W-t Wm W-t Wm Wt Wm

Explanation / Answer

For getting into the question firstly we should have a brief knowleadge of what actually immunodeficiency means ...

Definition:- it's a condition in which a body is unable to produce enough antibody to fight bacteria and viruses often resulting in infection.

Now, according to the data given it is said that t cells are normal in number in wm mouse but according to immunodeficiency study In any immunodeficiency disease ability to produce T cell is compromised n if it's given that they r normal so now we can go to other factors.

It's given in the question that there is a single Gene defect which is causing immunodeficiency but that Gene is not affecting t cell n other immune cell production. Now it's noted that all infections are cleared except heliminthic parasite infection.

Let's talk about how does helminth infection proceed in organism....firstly the interaction between helminth and host's immune system provokes particular immunomodulatory and immunoregulatory mechanisms that ensure survival in host for years.however these changes might impair the immunological responses to bystand bacterial,viral,protozoal pathogens and also vaccination.Modulation of the immune system by infection with helminthic parasite is proposed to reduce the level of allergic responses.

So according to this mechanism:-

a) The problem in wm mouse is it was not able to produce normal number of t cell when it's infected with helminthic parasite. And according to test results given in table 2.A we can clearly see that cytokine production for wt is equal in all 4 levels where as it's fluctuating in case of wm n at the end it suddenly shoots up.Its said that irregular levels of cytokine indicates immunodeficiency disorders that according to question are accuring in wm mice.

b) The three possible candidate are:-

1) IFN lamda

2) IL-5

3) the third possibility can be that it's an acquired immunodeficiency.

For 1) and 2) we say that the immunodeficiency is associated with impaired production of both 1) and 2). Where IFN lamda is a driving force in disease progression.

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