• Function of HLA Antigens

• Category 1 Immunological Problems: HLA Compatibility as a Cause for Recurrent Spontaneous Pregnancy Loss

• Category 2 Immunological Problems: Autoantibody Response to Phospholipid Adhesion Molecules

• Category 3 Immunological Problems: Autoimmune Response to Nuclear Components

• Category 4 Immunological Problems: Autoimmune Response to Sperm Antigen

• Category 5 Immunological Problems

  • Chapter 1: CD 56+ Natural Killer Cells

  • Chapter 2: CD 19+ 5+ B Cells (1)

  • Chapter 3: CD 19+ 5+ B Cells (2)

Introduction

There are 30 different types of lymphocytes (CD designations) that make up the immune system. A balanced functioning of these white blood cells keeps a person healthy. Two of these cell types can cause infertility, implantation failures and miscarriages (see diagram below). Women are born with these cell types. In some women, they increase in numbers and activity and result in reproductive failures.

	The Immune System has 30 Different Kinds of Lymphocytes
	Two Types Can Damage Pregnancies
		Antibodies to Hormones (Chapter 2)
Tumor Necrosis Factor Alpha (Chapter 1) Antibodies to Neurotransmitters (Chapter 2)

Types of white blood cells include the following:

1. TH-2 ("T Helper 2")
   The response is a balanced correct response during pregnancy (Category 1).
   
   
2. TH-1 ("T Helper 1")
   The response is a cyto-toxic autoimmune response that can lead to infertility, implantation failure and miscarriage (categories 2, 3, 4 and 5).
   
   
3. CD3, CD4, CD8
   Control production of blocking antibody response; a correct response.
   
   
4. CD19⁺ 5⁺
   Produce antiphospholipid antibodies (Category 2) and anti-DNA and histone antibodies (Category 3). It also produces antisperm antibodies.
   
   
5. CD56⁺, CD57⁺
   Are natural killer cells.
   
   

Please see A Guide to Interpreting the Results of the Reproductive Immunophenotype for more information on lymphocytes.

Chapter 1: CD 56+ Natural Killer Cells

1. Increase in number 2-12% normal. Above 12% see infertility and pregnancy losses.
2. Increase in cytotoxicity in NK assay. Cytotoxicity above 15% at 50:1 can damage the embryo.
3. These cells usually reside in the blood; however, in 2% of women they are so activated they live in the uterus. This is determined by an endometrial biopsy on day 26 of a normal cycle and by the TJ-6 test which finds women whose Natural Killer Cells have become the most activated.
4. They produce toxic Cytokines (TH-1 cytokines) including Tumor Necrosis Factor (TNF) Alpha.

Consequences

1. Prevent implantation.
2. Cause miscarriages by damaging the placental cells, causing decidual necrosis, damage the yolk sac.
3. Later in pregnancy they cause slowness of the heart rate of the baby, cause an irregular shaped gestational sac that is smaller than normal and amniotic fluid volume that is too small.
4. They induce subchorionic hemorrhages which can cause spotting, bleeding and can be seen easily on ultrasound.
5. In some women they can affect the DNA in the eggs so that fragmentation, slow cell division, arrested cell division and poor quality embryos are seen.

Chapter 2: CD 19⁺5⁺ B Cells (1)

1. Normal numbers are 2% - 10%. Women with problems have increases in cell numbers above 10%.
2. These cells produce antibodies to hormones necessary for pregnancies to develop safely. These antihormone antibodies are against estradiol, progesterone, and Human Chorionic Gonadotropin (HCG).
3. These antibodies lower hormone levels and lead to luteal phase deficiencies, slow rising HCG levels when pregnant, poor stimulation during ovulation induction cycles and poor lining development by ultrasound evaluation.

At Ovulation or Recovery of Eggs
			TNF
DNA in Eggs
			Damages DNA in Eggs by Apoptosis - Spot Welds the DNA so that it Divides Poorly
		Egg	Embryos Show Slow Cellular Division, Fragmentation of Cells, Inclusions in Cells. This Causes Failed IVF, Implantation Failure & Ovarian Failure

Before Implantation
		NK Cells Resident in Uterus
TNF Alpha
Causes Apoptosis of the DNA in the Embryo Leading to Spot Welding of the DNA Embryo Grows Slowly and Dies. Embryo Never Attaches. Placental Tissue Grows With No Embryo Seen.

After Implantation TNF Alpha Damage
TNF
Decidual Necrosis					Yolk Sac Damage
Subchorianic Hemorrhage					Slow Heart Beat
						Irregular Shape Gestational Sac
Placental Cell Death
						Too Little Amniotic Fluid

Consequences

1. Resistant ovary syndrome or premature ovarian failure. Day 3 FSH and Estradiol levels are too high.
2. Poor egg quality in IVF. Fewer eggs recovered, slow division following IVG, fragmentation of embryos, poor quality embryos, fragile when frozen and thawed, multiple failed transfer cycles with no positive BHCG or slow rising BHCG.
3. Lining fails to develop adequate thickness, adequate layers or adequate blood flow to zone three.

Chapter 3: CD 19⁺5⁺ B Cells (2)

1. Normal numbers are 2 - 10%.. Women with problems have increases in cell numbers above 10%.
2. Produce antibodies to neurotransmitters, including serotonin, endorphins and enkaphlans.
3. These antibodies cause the ovaries to be resistant to stimulation, cause a poor lining to develop, interfere with the muscle development of the uterus, and prevent blood flow to the lining of the uterus and muscle at the time of implantation.
4. These antibodies can cause depression, fibromyalgia, sleep disorders, increasing PMS symptoms and night sweats.

Antibodies to Neurotransmitters
				Zones 1, 2 & 3 of endometrium on day of ovulation
Muscle cells
Serotonin
	Blood flow to Zone 3			Endorphins & enkaphlins are involved in the modeling of the 3 layers of endometrium Antibodies to these lead to a thin "teflon" endometrium without a blood supply
Serotonin needed to change muscle cells of uterus to accommodate a pregnancy Antibodies to serotonin leads to a uterus that does not accommodate a pregnancy

Consequences

1. Follicles stimulate poorly and require heavy doses of fertility drugs to awaken.
2. Endometrial lining is thin; it rarely gets above 7 mm.
3. Three zones of the endometrial lining do not develop.
4. Blood vessels do not enter zone three.
5. Uterine smooth muscle remains quiet and does not contract three times in two minutes.
6. Eggs are of poor quality, fertilize in vitro with difficulty, divide slowly or incompletely, are low grade embryos and embryos fragment.
7. Women are depressed, sleep poorly, panic easily and experience symptoms of achiness and fibromyalgia.