Immunology during Pregnancy

Immunology during pregnancy

The immune system is in charge of protecting the body against foreign bodies. This task is modulated during pregnancy since a maternal immune response at this stage could prove fatal for the fetus. Immunosuppression is a down regulation of the components of the immune system, which leaves the organism in state of susceptibility to infections.
During pregnancy, several factors contribute to a full term pregnancy. We need to take into consideration that the fetus is not fully compatible with the mother, which theoretically makes the baby a target for the immune system. One of the major reasons an immune response toward the fetus does not occur is that fetal trophoblast cells do not express MHC Ia antigens. These antigens are responsible for acute rejection of an allograft in humans (Veenstra van Niewenhoven et. al, 2003). Since the fetus does not express them, paternally-inherited MHC antigens will not be recognized as an incompatible allograft by the mother.
Another important factor during pregnancy is thymic involution. As a consequence of this involution, the amount of naïve T cells and thymus secretory factors decreases, thus promoting the survival of the fetus. The few thymocytes available during the pregnancy oversee the integrity of the mother’s immune system. However, the mechanism for this process still remains unknown.
Innate immunity is the mechanism that initially recognizes and responds to the presence of a pathogen; it does not increase with repeated exposure and does not discriminate between groups of similar pathogens. This system is neither specific nor precise, and its most important aspect related to pregnancy is that it does not create an immunological memory. Lack of such a memory benefits the fetus because it prevents future attacks of the immune system during the gestation period. Another factor that contributes to the tolerance of the non-compatible fetus is the shift away from type 1 cytokine production during pregnancy.
One major concern during pregnancy is the blood type differences between fetus and mother. Alloimmunization most often results from Rhesus (Rh) incompatibility between mother and fetus. If the fetus has a different type of blood, the mother may recognize it as a pathogen and in the following pregnancy with Rh factor incompatibility, the mother’s immune system will attack the red blood cells of the fetus. If the mother is Rh negative, she will not tolerate an Rh positive fetus and can create antibodies against the fetal blood. These antibodies will attack the RBC’s of the next Rh incompatible fetus, and the fetus will develop anemia. This hemolytic anemia can cause mental retardation, illness and in extreme cases newborn death. It is a type 2 hypersensitivity that involves an antibody-mediated reaction, which involves IgG antibodies against cell surface receptors.
Our entire discussion is focused on how the fetus survives during pregnancy. Consequently, it is not surprising to see decreased aggressiveness of autoimmune diseases in immunomodulated pregnant women. Thus, many of the mechanisms of immunosuppression remain unknown, yet they have proved to be highly efficient in protecting the fetus.

Clinical Applications:
An important clinical application in pregnancy immunology is immunotolerance, the basis for successful implantations. Pregnancy is not a classical graft vs. host reaction; however, it involves specific compounds derived from the embryo which modulate the immune response. This concept has been very important in the success of egg donation programs. However, it has its risks because egg donation is associated with a high incidence of pregnancy complications such as pre-eclampsia and intra-uterine growth restriction. Pre-eclampsia in mothers that participate in egg donation programs may occur mainly because the mother may lack the receptors for the proteins the placenta is using to down regulate the maternal immune system's response, therefore, lack of established immunological tolerance, resulting in an immune response against paternal antigens from the fetus and its placenta. However, gene sharing (HLA sharing) results in a more effective immunotolerance, decreases complications, and aids in avoiding miscarriage.

Multiple Choice Questions:
1. Expression of which of the following cytokines is correlated with impairment of embryonic and fetal developments(Choose best answer):
a. IL-1
b. IL-2
c. IFN-α
d. IL-17

2. One of the major reasons an immune acute rejection (similar to that of an allograft) toward the fetus is avoided is the fact that:
a. Involution of maternal thymus during pregnancy
b. Innate immune response of the mother is downgraded
c. Fetal trophoblast cells do not express MHC Ia antigens
d. Increase in the amount of naïve T cells and thymus secretory factors

3. Rhesus incompatibility is a type of ____________ that involves the attack of _____________.
a. Alloimmunity, red blood cells of fetus with same Rh as mother
b. Autoimmunity, red blood cells of fetus with different Rh than mother
c. Alloimmunity, red blood cells of fetus with different Rh than mother
d. Autoimmunity, white blood cells of fetus with same Rh as mother

Discussion Questions:
1. What would happen if the mother was not immunosuppressed during pregnancy?
2. How is an immune response towards the fetus avoided?
3. What is innate immunity, and how does it benefit the fetus?

Images:

Alloimmune hemolytic anemia, Rh incompatibility. Blood film. Note the polychromatophilic macrocytes (reticulocytes), the nucleated red cells, and the ejected erythroblast nuclei. Spherocytes are present. The intense erythroblastosis (nucleated red cells in the blood) is characteristic of Rh-mediated alloimmune hemolysis.



A: Rh-negative woman before pregnancy. B: Pregnancy occurs. The fetus is Rh-positive. C: Separation of the placenta. D: Following delivery, Rh isoimmunization occurs in the mother, and she develops antibodies (S) to the Rh-positive antigen. E: The next pregnancy with an Rh-positive fetus. Maternal antibodies cross the placenta, enter the fetal bloodstream, and attach to Rh-positive red cells, causing hemolysis.

Thymic involution and loss of functional thymic tissue. (A) With increasing age, functional thymic tissues (medulla and cortex) are replaced by fat.

References:
Amoudruz P, Taku-Minang J, Sundstrom Y, Nilsson C, Lilja G, troye-Blomberg M, Sverremak-Ektron E. Pregnancy, but not the allergic status, influences spontaneous and induced interleukin 1b, (IL-1B) (Il-6) (Il-10) and Il-12 responses. Immunology [ 10.111 j.1365-2567.2006. 02400.x 2006. 119: 18-26.
Chaouat, G., Menu, E., Clark, D.A., Dy, M., Minkowski, M. and Wegmann, T.G. Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy. J. Reprod. Fertil. 1990. 89, 447±458.
Formosa M. The paradox of pregnancy: an update on the immunology of early pregnancy. Malta Medical Journal. 2008. 20, 02.
Geha R, Rosen F. Case studies in immunology: A clinical Companion. New York. Garland Sciences. 2007.
Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstetrics and Gynecology. 2008. 112-164.
Murphy K, Travers P, Walport M. Janeway’s Immunobiology. New York: Garland Sciences; 2008.
Piccinni MP. T-cell cytokines in pregnancy. American Journal of Reproductive Immunology. 2002. 47, 5: 289-94.
Veenstra von Nieuwenhoven AL, Heineman MJ, Faas MM. The immunology of a successful pregnancy. Human Reproductive Update [ 10.1093] 2003. 9, 4: 347-357.

Welcome

This is an Immunology Blog created for the first year medical students from San Juan Bautista School of Medicine at Caguas PR. This blog was created to publish their works about special topics in Immunology.

Tumor Immunology

SUMMARY

Cancer is a multifactorial disease involving genetic and environmental components. The immunological aspect of cancer is known as tumor immunology. This discipline is comprised of the study of host defenses against tumors, usually studied by tumor transplantation (Murphy 2008). A tumor is an ectopic uncontrolled cell growth (Harvey 2008). Tumor cells avoid immune recognition in a variety of ways such as low immunogenicity, antigenic modulation, tumor treated as self-antigen, tumor induced privileged sites, and tumor induced-immune suppression. Benign tumors are tumors that have not spread to other parts of the body. Progressive growth and invasiveness are characteristics of malignant tumors (Murphy 2008). Tumor classification is based on embryological origin. Carcinomas are tumors from endodermal and ectodermal origin. Sarcomas are from mesodermal, and in special cases from ectodermal origin. Leukemia and lymphomas are tumors that come form hematopoietic cell lineages. However, leukemia proliferates individually and lymphomas proliferate as solid tumors (Murphy 2008).
The immune system has the ability to detect and eventually destroy tumor cells, which is a process known as immune surveillance and is divided in three phases. Immune surveillance occurs in immunocompetent individuals, but when the immune system is comprised, tumor cells escape. The first phase is the elimination phase where tumor cells are recognized and destroyed. The second phase is an equilibrium phase, which follows if elimination is not completely successful. A process of immunoediting occurs in which tumor cells undergo changes or mutations for their survival. When these tumor cells have accumulated sufficient mutations they enter the third phase, the escape phase, where they elude the immune system being able to grow and become clinically detectable (Murphy 2008).
Some of the tumor cell mechanisms to escape CD8 detection help NK-cells to detect tumor cells. For example, tumor cells can lose the expression of MHC class I molecules, which decreases susceptibility to cytotoxic T cells. MHC class I molecule is a NK-cell inhibitor and as the tumor loses the MHC class I molecule expression, tumor cells become more susceptible to be killed by NK-cells. (Harvery 2008, Riond 2009).
One widely used technique in tumor immunology is the development of monoclonal antibodies against tumor-specific antigen (TSA). However, this technique only works on a specific type of cancer cell lineage. Once the monoclonal antibodies have been applied, it provides protection against tumor ‘X’ and only tumor ‘X’ cells. If the patient then develops tumor ‘Y’, with tumor ‘Y’ cells, a new monoclonal antibody will be needed. Another use for monoclonal antibodies is their tumor detection capacities. In the same way in which monoclonal antibodies can adhere to tumors by the TSAs, antibodies labeled with indium-11 can be used to detect the specific site of the lesions. Recurrent colorectal cancers detection is an example of this technique. The affected patient is injected with an indium-111-labeled monoclonal antibody against carcinoembryonic antigen, and the affected sites will be most noticeable in a radiography (Murphy 2008, Descotes 2009).
Vaccines have been developed to induce effective cytotoxic- and helper- T cell responses against viruses since cancers may develop from some virus exposures. Some of these cancers include liver cancer by hepatitis B, Hodgkin’s disease by EBV and cervical cancer by HPV. Vaccines have been developed to block some of these viruses, thus preventing the cancer. HPV vaccine been one of the most effective. The HPV vaccine contains purified inactive proteins from HPV 6, 11, 16, and 18, which are virus-like proteins that resemble the HPV virus. This vaccine is designed to elicit virus-neutralizing antibody responses that prevent initial infection with the HPV types represented in the vaccine (Murphy 2009).
References: 1. Murphy K, Travers P, Walport, M. Janeway’s Immuno Biology. 7th ed. New York: Garland Science; 2008: 683-685.2. 2. Harvey, Richard A. Immunology. Baltimore: Lippincott’s, 2008. 3. University of Virginia School of Medicine. White Cell Disorders. http://www. med-ed.virginia.edu/courses/path/innes/wcd/index.cfm. Accessed April 20, 2010. 4. Riond, J. IN vivo major histocompatibillity complex class I (MHCI) expression on HHCIIow tumor cells is regulated by gammdelts T and NK cells during the eary steps of tumor growth. Cancer Immunology. 2009; 2:9-10.
5. Descotes J. Immunotoxicity of monoclonal antibodies. Mabs. 2009: 1(2):104-11.

DISCUSSION QUESTIONS

1. Describe the mechanisms of immune evasion by tumor cells.
2. Discuss the three immune surveillance phases.
3. What are current tumor therapies?


MULTIPLE CHOICE QUESTIONS

1. According to the immune surveillance theory,
a. antibodies arise during fetal development that can destroy tumors.
b. cancer cells rarely arise within a normal individual.
c. tumors arise only if malignant cells escape immune detection.
d. innate immune responses eliminate specific tumor cell antigens

2. Monoclonal antibodies in tumor immunology involves the creation of antibodies against
a. Complement bound antigens
b. Specific tumor antigens
c. Membrane receptors of tumor cells
d. Undifferentiated cells

3. A new method to reduce the incidence of certain cancers such as cervical cancer involves
a. administration of tumor necrosis factor to the cervix
b. stimulation of antibody-mediated cell lysis of cervical tumor cells
c. use of patient’s tumor cells to develop an individualized vaccine
d. vaccination against human papillomavirus

Reference for multiple choice questions (excerpts taken from):
Harvey, Richard A. Immunology. Baltimore: Lippincott’s, 2008. (pp. 309-310)

CLINICAL APPLICATIONS

A. Lymphomas

Clinical Vignette: A 50-year-old woman presents to your office with a one-month history of fever, night sweats, and chills. She also has labored breathing and a persistent cough. In the physical exam, you find that the patient has recently lost 10 pounds with a concomitant loss of appetite. Cervical, supraclavicular, and axillary lymph nodes are enlarged and non-tender. Excision biopsy from one of the enlarged lymph nodes(lymphadenopathy) was performed, and histopathological examination reveals Reed-Sternberg (RS) cells. A computerized tomography (CT) scan revealed multiple lymphadenopathies in the axillary and chest regions. A complete blood test reveals anemia.

Pertinence for the medical practice:
Malignancies of lymphoid cells, such as leukemias and lymphomas, arise from cells of the immune system. Lymphomas are solid tumors within lymphoid tissues. Leukemias are cancers of immune system cells outside of central and peripheral lymphoid tissues. Hodgkin’s disease is a type of lymphoma that appears in 8000 patients in the United States each year. It is found in lymph nodes, spleen, liver, and bone marrow tissue. One of the first signs of Hodgkin’s disease is often a non-tender enlarged lymph node. An excision biopsy is a biopsy where the doctor removes the entire lymph node, and if Reed-Sternberg cells are found, a diagnosis of Hodgkin’s lymphoma can be made. A Reed-Sternberg cell is typically an enlarged clonal B-cell with a bilobed nucleus and prominent nucleoli giving it an “owl’s eyes” appearance. Swelling of lymph nodes inside the chest can compress the windpipe and cause labored breathing and cough. Below is a picture showing a Reed-Sternberg cell.

References:

1. Sonmez, Mehment. Case Report: Familial Hodgkin’s Lymphoma from the Perspective of HLA. Internal Medicine. 2010.

2. American Cancer Society. How is Hodgkin Disease Diagnosed? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3x_How_Is_Hodgkin_Disease_ Diagnosed.asp?sitearea. Accessed April 20, 2010.

3. University of Virginia School of Medicine. Lymphoma: Hodgkin Lymphoma (Part 1). Available at:
http://www.med-ed.virginia.edu/courses/path/innes/wcd/hodgkin.cfm. Accessed April 20, 2010.

4. Medline Plus. Hodgkin Disease. Available at: http://www.nlm.nih.gov/medlineplus/hodgkindisease.html#cat5. Accessed April 20, 2010.

5. Access Medicine. Harrison’s Principles of Internal Medicine, 17e. Available at: http://www.accessmedicine.com/content.aspx?aID=2890082. Accessed April 20, 2010.

B. Sarcomas (Schwannomas)
Clinical Vignette: A 55 year old male is visiting because of a 5 month progressive hearing loss, weakness of the right lower limb, and loss of pain sensation on the left lower limb. Upon physical examination, you notice multiple café-au-lait spots(image below) and neurofibromas. He recalled his father had the exact same spots. When performing reflex signs, you find that they where +1. You suspect Neurofibromatosis with schwannomas. A Karyotype is made using FISH and you conclude that the gene for NF-1 protein on chromosome 17 is missing. A s-100 immiunohistochemical test for schwannomas is positive.




Pertinence for the medical practice:
NF-1 protein is a tumor suppressor gene, its role is in deactivating ras proteins which are involved in the cell cycle. Neurofibromatosis(Von Recklinghausen disease) is an autosomal dominant disorder characterized by the development of café-au-lait spots(image below) and tumors of the peripheral nerves(schwannomas) and cranial nerve 8 (acoustic neuromas). Schwannomas proliferate inside the nerve sheath and evade detection from the immune system.
The progressive hearing loss is due to schwannomas on the cranial nerve 8 the vestibulocochlear, some unequilibrium signs may also be present. The weakness and sensory loss are due to schwannomas affecting the corticospinal tract and spinothalamic tract, which relay motor and sensory function to the limbs. The karyotype and S-100 test confirm your diagnosis, The karyotype by showing the NF-1 gene deletion and the S-100 antigen test provides insight on nerve damage, usually when the Patient has S-100 levels above 0.50 µg/L.


References:

1. Patel S. R., Benjamin R. S. Soft Tissue and Bone Sarcomas and Bone Metastases. Access Medicine website. 17 ed. Available at: http://www.accessmedicine.com/content.aspx?aid=2866942. Accessed April 20, 2010.

2. Peck P. S-100 Measurement in Patients With Minor Head Injury Can Reduce CT Use. Medscape Today. 2005. Available at: http://www.medscape.com/viewarticle/497751. Accessed April 20, 2010.

3. Lancaster E, M.D., Ph.D., Elman L. B., M.D., and Scherer S. S., M.D., Ph.D. A patient with Neurofibromatosis type 1 and Charcot-Marie-Tooth Disease type 1B.
Pub Med Central. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847649/?tool=pubmed. Accessed April 20, 2010.

4. Jayarama M, MD. Schwannoma, Cranial Nerve. Emedicine. 2010. Available at: http://emedicine.medscape.com/article/336141-overview. Accessed April 20, 2010.


C. Carcinomas
Clinical Vignette: A 23 year-old Puerto Rican male presents with an enlarging neck mass, difficulty swallowing and 20 pound weight loss. He does not complain of night sweats, fever, or shortness of breath. The physical exam showed a 6.5-cm firm, but non-tender neck mass on the left side, hepatomegaly, and swollen lymph nodes located in the supraclavicular, right axillary and bilateral inguinal regions. As the physician, you order a complete blood count (CBC) test, a chest x-ray and a CT scan. The CBC results were normal and the HIV and hepatitis panel were negative. The chest x-ray demonstrated a right mediastinal mass and the CT showed diffuse lymph node disease or lymphadenopathy (LAN) in the mediastinal, peritoneal, and retroperitoneal regions and numerous liver metastases. As a result, you perform a fine-needle aspiration (FNA) biopsy of the neck mass, which reveals atypical lymphoid cells, and subsequently, an excision biopsy showed anaplastic carcinoma of the thyroid (Grigorian and Powell 2003).



Pertinence for the medical practice:
Carcinomas are tumors that develop from ectodermal or endodermal tissues, such as skin and glands. They are the most common type of malignant tumors and include cancers such as breast, colon, and lung (Harvey 2008). Carcinomas can be classified in many ways, but the following are three major types: basal cell carcinomas, squamous cell carcinomas, and melanomas. Basal cell carcinomas are malignant neoplasms or new growths derived from non-keratinizing cells that originate in the basal layer of the epidermis. Squamous cell carcinomas are malignant neoplasms derived from keratinizing cells in the suprabasal epidermis. Melanomas are the most aggressive type of skin cancer (Paek). The American Cancer Society estimates that in 2006, 111,900 new cases of melanoma were diagnosed. Risk factors for these types of carcinomas include exposure to sun, ultraviolet radiation, or therapeutic radiation , age, fair skin , many moles, or a history of skin cancer in the family. Below is an image of how these different types of carcinomas appear on the skin. Sadly, there are carcinomas that develop for unknown reason such as anaplastic carcinomas of the thyroid like the one described in the clinical vignette. Fortunately, this type of cancer accounts for less than 2% of all thyroid cancer (Rockoff 2010). However, doctors should advise their patients to get screened frequently since it is the best way to detect tumors before they spread and cause cancer.

References:
1. Grigorian B and Powell L. Clinical Vignettes. Journal of General Internal Medicine. 2003;18:54-55. Available at: http://www.springerlink.com/content/w4168j9133788261/. Accessed April 20, 2010.
2. Konstantakos A.K. Thyroid, Anaplastic Carcinoma. eMedicine website. 2009. Available at: http://emedicine.medscape.com/article/283165-overview. Accessed April 20, 2010.
3. Rockoff A. Skin Cancer. Medicine Net website. 2010. Available at: http://www.medicinenet.com/skin_cancer/article.htm. Accessed April 20, 2010.
4. Paek S. C. Dermatology. Access Medicine website. Available at: http://accessmedicine.com/content.aspx?aID=2982816&searchStr=melanoma#2982816. Accessed April 20, 2010.
5. Harvey, Richard A. Immunology. Baltimore: Lippincott’s, 2008.

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