Dr. James Evermann
Lecture 8: Basis for Immune Response in Livestock
Basis for
Immune Resistance in Livestock
The Immune Response is divided into three general types:
1. Antibody-mediated responses (humoral immunity)
During embryonic development, approximately mid gestation for most animals, is when the cells are starting to form in the bone marrow. Some cells travel to the thymus and others stay in the bone marrow and they start to produce lymphocytes. B-cells are derived directly from the bone marrow and produce antibodies. This is the humoral immune response.
2. Cell-mediated responses (cellular immunity)
The other cell population travels through the thymus and is named T cells. These cells derive the T killer cells. Antibodies take care of extracellular parasites, bacteria in the blood, and free on mucosal surfaces. Antibodies effectively kill extra cellular bacteria.
Other infectious agents: viruses, protozoas are killed by the T-cells, the killer cells. They attack parasites that are inside cells. So the immune response has developed two unique components: antibodies to take care of pathogens outside the cells (antibody) and killer cells that kill pathogens inside the cells. This is important because inactivated vaccines or killed vaccines only stimulate half of the immune response, the B-cells. When using an inactivated vaccine for viral infections you need to be cautious. These are not stimulated T-cells. This is the most common reason why vaccines sometimes don’t work. They are not stimulating the right immune response.
3. Tolerance (lack of humoral and/or cellular immunity)
This is the lack of humoral and/or cellular immunity. An example of that, you recall, was BVD infection. The pregnant animal acquires infection during 90 to 120 days gestation. The calf is tolerant. It does not develop an immune response to that particular virus ever. Consequently it is perpetually infected and shedding virus into the environment. This kind of animal you would want to cull from your herd because it can never be made to recognize its tolerated pathogen.
return to top of this section of notes | notes indexComponents of the Immune Response
Antibody is a protein referred to as immunoglobulin and is derived from lymphocytes originating from the bone marrow (B cells). This form of immunity is essential for extracellular pathogens. Antigen is a foreign material, which is recognized by the Immune Response following antigen processing in phagocytes (macrophages). Well, this means you started out with an antigen. It is broken down into smaller antigens within the macrophages, referred to as processing. The macrophages then deliver it to either the B-cell population or the T-cell population. You either get antibodies, or you have killer T-cells. So if you were to ask is there an essential cell in this population that we need to have, you would have to say the macrophages are really important because they break down the antigen into bits that can be recognized by B-cells or T-cells.
Cell mediated Immune Response (T-cells) is directed to target cells throughout the body which have altered cell membrane antigens. This form of immunity is essential for control of intracellular parasites such as viruses, protozoa, and some intracellular bacteria such as B. abortus and M. paratuberculosis. CMI is considered to be the major immune defense against tumors. What it does is it starts to express antigens at the surface of the cell so that the corresponding T-cells recognizes them. That is what stimulates the T-cell into action. So you have to say that this is a receptor mediated function. If you don’t have this kind of recognition, what happens? Have you ever heard of autoimmunity? Autoimmunity is where these T-cells start killing normal cells. Systemic lupus in humans is an example of that.
Lymphoid organs are distributed throughout the animals body (Figure 1). These organs regulate the production and differentiation of lymphocytes. Lymph nodes are strategically placed on lymphatic channels so as to trap antigen carried through the lymph. Lymph flows from tissues to lymph nodes and recycles through the bloodstream (Figure 2). Probably your main lymphoid organ are your salivary glands, your thymus, your spleen, and your bone marrow. Virtually every body tissue has lymph nodes in it. There are lymph nodes in the genitourinary system, the intestines, mammary glands, and the respiratory tract as well. So basically, lymph nodes are throughout the body. And the lymph nodes have both B-cells and T-cells within them. Lymph nodes regulate the production and differentiation from the lymphocytes. And when we say differentiating the lymphocytes, what we are referring to here is a differentiation of B-cells or T-cells. That is what that refers to. Now this is interesting because the lymph nodes give rise to lymph and the lymph has all the lymphocytes in it, and it now circulates throughout the body. So basically, we have resident B-cells and T-cells, and then you also have circulating.
Phagocytosis is the process of capture and destruction of foreign material. The two leading cells in this process are neutrophils and macrophages (Phagocytes). Phagocytes are aligned along respiratory and digestive tracts and are important in all forms of tissue injury and subsequent tissue repair. Phagocytes play a valuable role in immune defense by directly attacking and destroying bacteria in tissues and in blood (bacteremia). Macrophages are an important link between natural immune defense and acquired immune defense. The acquired immune defense is comprised of macrophages that process antigen (also referred to as antigen processing cells) and lymphocytes that are stimulated by specific antigens resulting in either sensitized B cells (antibody) or sensitized T cells (cell mediated immunity). The natural immune defense the antigen enters the body and the macrophage takes care of it. It either processes it and kills it, or can process it and get it ready for the acquired immune response. The major difference here is that there is no memory with a natural immune defense – no memory at all. Once these processed antigens alert the B-cells and the T-cells, this acquired immune defense then has memory. What I mean by memory is when that B-cell or T-cell sees that antigen again, it kicks into action immediately, and I am talking within hours. This is an important concept to recognize. The macrophage serves as both natural immune defense as well as acquired immune defense. And the acquired immune defense has memory cells associated with it. If B-cell or T-cell becomes alerted, they are referred to as being sensitized.
Immunoglobulins - There are various classes of Ig which have specific functions. The major classes are:
Cytokines/interleukins are regulatory proteins secreted primarily by lymphocytes to facilitate interaction between other lymphocytes and macrophages e.g. IL-2, IL-12, CSF, TNF. The reason that these are important is because they help stimulate key cytotoxic cells. If we continue to use inactivated products – I have already told you that inactivated vaccines only stimulate half the immune response, the B-cell response. If somehow we can genetically make that vaccine so that you have it killed, but are able to include these IL-2 and IL-12 into that vaccine, what you then can do is have a killed product to stimulate both your B-cells and your T-cells. That is currently where vaccine production is going. They are trying to do this. Unfortunately, the half life of these interleukins is only about 5 minutes. Pretty expensive stuff. It doesn’t last very long in the body.
Interferon is glycoprotein produced by macrophages, lymphocytes and epithelial cells in response to viral infection.
return to top of this section of notes | notes indexSpecific Functions of the Immune Response
Colostrum represents the accumulated secretions of the mammary gland over the last few weeks of pregnancy. It is rich in IgG (65-90%) with variable levels of IgA and IgM. Form of passively acquired immunity (short-lived). Failure of passive transfer (FPT) results in livestock that fail to absorb adequate levels or ingest insufficient or poor quality colostrum. FPT may result in bacteremia and/or viremia (virus in blood).
Mucosal immunity is a form of local immunity on the body surfaces of the respiratory, intestinal and genital tracts. IgA together with a secretory component (peptide) forms secretory IgA. Short lasting immunity or dependent upon the continual presence of the bacteria and/or virus. A really important concept – mucosal immunity or localized immunity, or surface immunity versus systemic immunity or blood. Now the best example of this, as we look at our gut and small intestine, is Peyer’s patches within the gut. These are really local lymph nodes and they secrete IgA into the gut. This is what protects the gut all the way from the small intestine down to the cecum. So it is a form of local immunity and it is acquired because it requires the continual presence of the bacteria or the virus. An oral vaccine that we give to an animal, whether it be a dog or a cat, calf or horse –that is what provides continual presence, that oral vaccination. It usually lasts anywhere from three weeks to three months.
A gradient of infection is observed in respiratory infections with aerosol droplets (Figure 3) and the intestinal tract with enteric bacteria and viruses dependent upon level of mucosal immunity, size of particles, temperature, etc. The upper respiratory tract includes infections anywhere in the nares, the lower throat area, and then the trachea. Anything into the bronchi and into the lungs is referred to as the lower respiratory. Pasteurella, which is a common opportunistic infection is a commensal of the nares. It is an opportunistic infection if it goes down into the trachea and the lower airways. Of course this is enhanced if you have viruses, such as IBR, PI3, or respiratory syncytial virus. So any infection that comes from another animal, if it is a droplet, and it contains numerous bacteria, normally gets stopped right within the nares and/or the upper respiratory tract. A lot of respiratory infections are self-limiting and you normally do not see them progress into pneumonia. The smaller the particle the greater the tendency to get into the lower airways , and you can see how that could enter the nasal epithelium and go down the upper respiratory tract, versus the larger droplets. So this is what is referred to as a gradient of infection as observed with aerosol droplets.
Opsinizing antibody is a type of antibody that coats particles, such as bacteria to promote phagocytosis. Usually the antibody is of the IgG class. (The universal symbol for antibody, by the way, is an upside down "Y"). So for opsinazation to take place, you need a bacterium, antibody that is coating it, and a macrophage. The antibody coating aids the macrophage in engulfing the bacterium, thus the result is phagocytosis.
Neutralizing antibody is a type of antibody that specifically blocks virus receptor sites on the virus preventing attachment to target cells in the body. Without a target cell for infection, the virus becomes inactivated (noninfectious).
Lactogenic immunity is a form of local immunity in milk (post colostrum) that bathes the intestinal tract and prevents colonization by virulent bacteria and neutralized viruses passing through the gut. This can be IgG or IgA, but the important thing is it is derived from the dam.
Tolerance refers to specific unresponsiveness to a given antigen. Can be achieved by antigen exposure to very immature animals (BVD virus in utero), low dose antigen, high dose antigen, or antigen delivered to Immune Response that cannot be processed properly. May affect either B cells (antibody) or T cells (cell mediated immunity).
When we talked about immune response, I tried to emphasize the importance of the two arms of the immune response, the humoral arm and the cell-mediated arm. They have each developed for an obvious purpose. Humoral immunity, is B-cell directed and it is primarily directed against exogenous or antigens outside the cells, and most bacteria are in that classification. Now your cellular immunity is primarily T-cell mediated. This is directed primarily toward endogenous, or antigens inside cells. This classification applies to all viruses and certain bacteria that are intracellular such as Johne’s or Bangs.
I have given you a diagram to include in your notes. Most of the B-cells and T-cells are derived in the bone marrow. The B and T cells develop from the multipotent stem cell. This stem cell can also differentiate into myeloid, which are macrophages. (Erythroid is red blood cells). And from the population of multipotent stem cells, you get lymphoid stem cells which then become all the lymphocytes. These are referred to as white blood cells. Now there is a subpopulation of lymphoid stem cells that is referred to as the null cell. It does have killer activity, but it is not specific, and has no memory. This is thought to be a cousin to the macrophage.
So then basically we have a cell that traffics through the lymphoid system, becomes a stem cell, then becomes a pre-B or a pre-T cell. The pre-B goes into the gut and associated lymphoid tissue, while the pre-T goes through the thymus, to mature. They differentiate into naïve B-cells or naïve T-cells, and they wait for an antigen. When they find an antigen it results in antigenic stimulation. An antigen can be a bacteria, a virus, fungi, or it can be just about anything foreign to the body, to alert the B-cells and T-cells.
The mature cell populations would look like plasma cells, which are your mature B-cells that produce antibodies. Additionally there would be memory B-cells. When they see an antigen again, they produce more plasma cells. Within the T-cell population there are cytotoxic T-cells (the T-killer cells), the helper cells, and the memory cells which produce more T-cells and helper cells. This is the basics of immunology.
The next figure is the usual scheme that follows vaccination. Notice, this only speaks to the humoral side, the antibody production, of the immune response. The vaccine actually acts as the antigen. The initial response is the primary immune response. Stimulation of the B-cells and T-cells occurs in the lymph nodes and spleen because that is where the T-cells and B-cells are waiting for the antigen. The vaccine or infection usually travels through the lymph while the lymph nodes and spleen act as filters to pick up the antigens. What results initially is a low-level antibody response and a very low level T-cell response. The beauty of the immune response is the memory. The next time the animal sees this antigen, whether it is a vaccine or infection, a booster immune response develops. You get a booster immune response in the B-cells, and they may have to recruit cells from the bone marrow, or you get a memory from the T-cells, and they get recruitment from the thymus. So basically you get amplification of your antibody and you get amplification of your T-cells. Generally it takes about three days before you can see a demonstrable immune response, and it is full bore after about 10-14 days. That is why normal boostering of vaccines is usually set at two weeks to allow the initial primary immune response to take effect. The secondary immune response can be anywhere after 14 days. The early protection within three days includes macrophages and interferon but not an acquired immune response.
Question: Does passive transfer come from the mother or does it come from failure to
suckle?
Answer: It can be either the failure to ingest or poor quality colostrum. A first half
heifer or a mare foaling for the first time is going to have low levels of IgG in her milk
because she probably has not seen as many antigens as a 4 or 5 year old. So the older the
animal is, the more antibodies is has, and the better quality of their colostrum. There is
also an indication that some breeds of dairy cattle have poor levels of colostrum. I have
heard that Holsteins, for instance, might have a poor level of colostrum than say a
Jersey. And so therefore, Holstein calves, it doesn’t hurt for you to augment their
colostrum with another source of colostrum. That is genetic. So, poor quality colostrum
can be lack of exposure of that animal, or it can be genetic, or the calf does not ingest
enough. So there are two reasons for that.
References
Hoopes and Thwait, 1997, pp 49-73.
Tizaid IR: Veterinary Immunology: An Introduction, Fifth ed., 1996.
Walker PB: Staying Alive: The World of Immunology. Compen Vet Tech 19:411-418, 1998.
Evermann JF: Immunology of bovine pregnancy: Vulnerability to infectious diseases. Am
Assoc Bov Prac Proc 26:101-104, 1994.
Figure 1. Major lymphoid organs of animals (From Tizard, 1996)
Figure 2. Circulation of lymphocytes from lymph (From Tizard, 1996)
Figure 3. Gradient of infection as observed with aerosol droplets in the respiratory tract (From Tizard, 1996)