Australia´s National Infertility Network
The Immune System and Infertility
Fact Sheet 02
Couples trying to have a baby may be frustrated by both a failure to conceive and
a failure to maintain a pregnancy once conception has occurred. Over the past few
decades it has become increasingly apparent that immunological factors make a
substantial contribution to these two clinical problems.
The body’s immune system includes among its functions the ability to distinguish
self from non-self. This ability (probably not as absolute as once believed) is cru-
cial in the recognition of ‘foreign’ or threatening invasion by infection or cancer cells.
In some instances (called autoimmune diseases) the immune system recognises
‘self’, and that recognition leads to inflammation, damage and disease.
Pregnancy is a unique situation in which the placenta (recognisable as ‘non-self’, or
separate from the mother) invades the lining of the womb and is a potential threat
to the well-being of the mother. The mother’s immune system must recognise that
threat, but also respond in such a way that does not eliminate it. The mother’s im-
mune system is critical in establishing the relationship between the mother and the
foetus that allows both to flourish.
bodies can have their own harmful effects is currently impossible to prove in any in- too – on both the placenta and the foetus.
dividual. Anti-ovarian and anti-testicular (type 2). In normal pregnancy, substances antibodies can be detected in the blood of individuals with ovarian and testicular fail- Antibodies to the ovary,
ure, but the tests are neither sensitive nor testis and sperm
specific (the antibodies are also found in that it becomes ‘type 2 dominant’. This is because type 1 responses are potentially About seven per cent of the population suf- it is not known if they are the cause or ef- fect of the problem) and by the time the stage in their lives, and some have life-long diagnosis is made, it is usually at the stage eases that are predominantly cellular such autoimmune diseases such as insulin depen- of complete ovarian or testicular failure, as rheumatoid arthritis tend to get better during pregnancy. But it also means that Failure of the testis or the ovary can result Sperm antibodies, whose cause is also un- pus (SLE) can get worse, and specific anti- AccessAustralia | Australia´s National Infertility Network | | [email protected]
The Immune System and Infertility
Fact Sheet 02
blood or sexual secretions, or both. The Antiphospholipid
tests (agglutination, or immobilisation — syndrome
using immunobeads) are difficult to carry out reliably and can only be done at a few specialist centres. In addition, by examin- ing the ejaculate in the post coital test, one can get some clues about the interaction ies measured as either ‘anticardiolipin antibodies’ or a ‘lupus anticoagulant’. If Because 25 per cent of APS give positive secretions. However in recent years it has results for only anticardiolipin (aCL) or become apparent that the successful treat- reproductive failure and no other clinical lupus anticoagulant (LA), it is important ment of otherwise unexplained infertility problems then this is termed the primary to test for both during investigations.
made the identification of these antibodies In general, the higher the level of anti- tosus (SLE) or Sjogren’s syndrome) it is cardiolipin antibody or the stronger the lupus anticoagulant, then the more likely It is still unclear if antiphospholipid anti- bility or binding to the egg, although it bodies have an affect on fertility per se. The ticardiolipin antibody and borderline lu- is still unclear what level of antibodies is antibodies occur in about four per cent of pus anticoagulant and poor obstetric his- significant to warrant treatment. It is now healthy Australians, and cannot therefore tories so the level alone cannot be relied are planning a pregnancy. They are found prove fertility in this situation. Previous can directly attack placental cells, and are lowed by artificial insemination or IVF. often used as markers of a possible immu- nological disorder. But they are most often unexplained infertility the current treat- assessed in the context of pregnancy loss.
sperm is injected into a single egg).
Antiphospholipid antibodies are reliable nancy, and are associated with early and IVF should still be treated to reduce the risk of miscarriage. It is also not known the genital tract. There may be instances of cytotoxic antibodies that actually kill the exposure of the female genital tract Antibodies affecting the
can affect the foetus is by passive trans- anxious to conceive as soon as possible. the level of maternal antibody declines. most successful treatments are intrauter- foetal heart block and heart failure.
The Immune System and Infertility
Fact Sheet 02
is certainly possible that the studies so far Natural killer cells
simply describe an ‘association’ between NK cell activity and reproductive failure productive failure will always be looking rather that a specific ‘cause-and-effect’.
search has focused on the ‘specific’ im- Interest in NK cell testing was stimulated by Alan Beer’s group in Chicago who, in 1996, first reported that blood NK levels are neither, but they are types of white that both testing and treatment is still failure. Since then over 30 publications very much ‘experimental’ at the frontiers part of the ‘nonspecific’ or ‘innate’ im- mune system. It is believed that in evolu- infertility and repeated unexplained IVF It is possible that increased NK cell ac- failure. Investigators have reported num- tivity is just one of a number of possible bers as a percentage of all lymphocytes, types, markers of activation (e.g. CD69) not recognised as ‘self ’ (e.g. infections and bioassays assessing ‘killing activity’. or cancer). Their killing capacity is also closely linked with cellular or type 1 im- uterine biopsy) assessing uterine NK cell Treatment of immunological
munity. As such they are potentially very causes of infertility
But there are important academic criticisms that is widely accepted as a treatable di- agnosis of ‘high NK cell activity’ would f the laboratory tests are difficult and measure (numbers of cells, cell subtypes, crease further to 70 per cent of all cells. placental cells, and they produce a range of potentially dangerous proteins called dominantly in the blood (called CD56dim) is different to that found in the uterus (called CD56bright), and the relationship plain the side effects, and experimental Thus, on the face of it, NK cells are likely causing both infertility and miscarriage. tive failure’, but there is no evidence so In spite of these valid criticisms, it is it is still unproven that NK cells do actu- ally cause reproductive failure. Evidence (see below) is still of poor quality and it involving NK cells or not) is certain to The Immune System and Infertility
Fact Sheet 02
Related Reading
c Antiphospholipid antibodies
m Recurrent miscarriage:
pathophysiology and outcome
Gatenby PA; Med J Aust 1994, 160:171-72.
b Natural killer cells and repro-
ductive failure – theory, practice
and prejudice
h An innate view
of human pregnancy
n Uterine natural killer cells,
implantation failure and recur-
rent miscarriage



sess its effect on major adverse cardiac events.1 Rates of1. Davidson KW, Rieckmann N, Clemow L, et al. Enhanced depression care forany cardiac hospitalization were 5% in the interventionpatients with acute coronary syndrome and persistent depressive symptoms:coronary psychosocial evaluation studies randomized controlled trial. Arch group vs 16% in the usual care group. The approxi- Intern M

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