REPRODUCTIVE IMMUNOLOGICAL DISORDERS NEW

Reproductive and Urinary system disorders• Foetal Acceptance Mechanisms• Reproductive system disorders• Urinary system disordes

Foetal Acceptance Mechanisms• Deciduas physical barrier• Privileged sites• Th2 type response• Reduced MHC expression• HLA-G Ag expression• Immunosupressive factors

Decidua Physical BarrierZygote sequestered in decidua• Specialized gestation tissue formed by

trophoblast invasion of the uterine tissue.

Decidua provides• Physical or anatomical barrier for

foetus • Prevents release of foetal and

trophoblast antigens into lymphatic vessels.  

Trophoblast-derived factorsNormal foetal growth supported by

• Suppressor cells and factors associated with deciduas and trophoblasts.

• Induction of trophoblast-derived immunosuppressive factors in maternal circulation and

• Recruitment of decidual suppressor cells promote foetal growth and development.

Privileged Sites• Anterior chamber of the eyes, testes,

brain• Mammary and subcutaneous fat pads• Thymus, matrix of hair follicles and • Uterus during pregnancy Factors rendering sites privileged • Tight junction between cells of the

tissue (blood-tissue barrier)

Privileged sites contExpression of Fas ligand (FasL)• Activated T cells expressing Fas commit

suicide by apoptosis when encounter FasL on their target.

• Higher concentration of suppressor cells at the site

• Soluble molecules secreted by tissue • Modulate local immune responses and

imprisonment of graft antigens within the location.

Th1/Th2 ResponsesTh2 cytokines (IL-4, IL-5, IL-10, IL-13)• Associated with the induction and

maintenance of allograft tolerance. IL-10 (Th2 cytokine) associated with • Deviation of immune response • Potent immunosuppressive effects in

allograft survival.

Reduced MHC expression• Syncytiotrophoblast do not express

class I MHC antigens which would trigger CTL activity.

High MHC class I expression associated with

• Recurrent spontaneous abortion• Decreased fecundity• Segregation distortions, altered sex

ratios• Reduced foetal growth rates and

maternal autoimmune disease progression.

HLA-G Ag ExpressionPaternal derived MHC antigen expressions• Downregulated through masking by

histocompatibility specific trophoblast antibodies or by

• Fibrinoids, fibrimucoid and immune complexes.

Paternal derived HLA-G molecules• Induce blocking antibodies that protect

allograft against maternal immune attack.

Immunosuppressivefactors• Maternal anti-foetal cytotoxic leukocytes are

blocked by IgG antibodies. • Women lacking these antibodies often abort

and immunized with paternal leukocytes. • Complement-dependent damage of the foetus

prevented by anti-complementary factors eg• Maternal cofactor protein (MCP), • Decay accelerating factor (DAF) and receptor

type I (CR I) which • Inactivate C3 – convertase in the complement system

activation pathway.

Reproductive &Urinary System Disorders

• HLA-G molecules• Phospholipids• Pregnancy induced suppression• Male infertility• Haemolytic diseases of new born• Autoimmune responses

HLA-G antigens On placenta cells derived from father

and functions in• Maintenance of maternal-placenta

immunological tolerance• Blocking antibodies protect and

stimulate growth of placental cells • Blocking antibodies not made when

couples share DQ alpha antigens

Consequencesof Lack of HLA-G

•Inadequate blocking antibody formation

•Ineffective camouflage of placenta

•Placenta cells failure to grow and divide

•Death of placenta cells

PhospholipidsPhospholipid molecules include• Cardiolipin ethanolamine, • Glycerol, inositol, phosphatic and

serine with• Important function in cell membranes

and intracellular organellesSerine and ethanolamine phospholipids • Allow the placenta to be securely

attached to the uterus during pregnancy

Antiphospholipid antibodies

• Disrupt cell functions and increase the clotting speed of blood with subsequent miscarriages

• Prevent secure attachment, cytophoblast formation into syncytiotrophoblast

Syncytiotrophoblast• Feeds the baby• Produces - hCG and progesterone• Grows throughout pregnancy• Delayed formation of

syncytiotrophoblast leads to pregnancy loss or implantation failure

Autoimmune ResponsesAutoantibody to DNA leads to • Inflammation in the placenta around

the embryo at implantation or in the placenta after implantation • Anti-dsDNA, SS-DNA, polynucleotide and

histone• Appear in women with eg lupus, rheumatoid

arthritis, Crohn’s disease• Antibodies cause inflammation in joints

and organs

Antisperm antibodiesWomen with infertility, implantation failures

and recurrent pregnancy losses• Have anti-sperm antibodies

associated with antiphospholipid antibodies

Antisperm antibodies inactivate sperms resulting in

• Couples unable to conceive normally and multiple failed pregnancies

Antibodies to Hormones• Against estradiol, progesterone and

human chorionic gonadotropin (HCG)Lower hormonal levels lead to • Luteal phase deficiencies • Slow rising HCG levels when pregnant • Poor stimulation ovulation induction cycles

and poor lining development• Antibodies to hormones may cause

depression, sleep disorders and night sweat

Antibodies to NeurotransmittersAntibodies to serotinin leads to• Uterus that does not accommodate

pregnancy with consequences of • Poor stimulation of follicles• Thin endometrial lining• Poor quality eggs• Depressed women, sleep disorders

and panicky

Pregnancy Induced Immunosuppression• Th1/Th2 response shift to Th2• Steroid hormone levels• CMI dysfunction, CD4/CD8 ratio alterations• Pyogenic infections (N. gonorrhoea and

S. pneumonia)• Viral infections (rubella, poliomyetlitis,

hepatitis, CMV,EBV)• Protozoan infections (cerebral malaria,

amoebiasis, toxoplasmosis)• Fungal and intracellular pathogens

(vaginal carrier yeast, miliary tuberculosis and listeriosis).

MALE INFERTILITY• Anti-sperm antibodies and

autoantibodies • B and T lymphocytes in semen• Granulocytes and m in ejaculates

HAEMOLYTIC DISEASE OF NEWBORN

ABO incompatibility• IgM isoagglutinins against ABO

antigens (allogeneic blood transfusions) IgG

• Agglutination, C1 activation and intravascular haemolysis, circulatory shock

Rh incompatibility• Rh-D mother with Rh-D+ foetus• Maternal IgG against foetal Rh-D+

alloantigens• First child spared and in second

pregnancy IgG cross placenta foetal circulation

• Alloimmunization increases with each incompatible pregnancy

• Anti-Rh D+ antibodies administered to Rh-D mother pospartum (>72 hrs)

GLOMEROLONEPHRITIS (GN)Initiators• Persistent infections; autoimmune

diseases, drugs/chemicals• Immune complex hypersensitivity disease• Non-inflammatory damage glomerular

epithelial cells• Inflammatory glomerular damage –

inflammatory cells proteases, ROI, cationic proteins + cytokines

Neutrophil-mediated damage• Augmented by platelets• M produce proinflammatory

substances•Prostaglandins, leukotrienes,

TNF-α and polypeptide growth factors

Post-streptococcal nephritis• Streptococcal-antistreptoccal IC

deposition in kidney• Autoantibodies against C3bBP

complex• Cause membrane proliferative GN type

1 tissues

• Autoimmunity perpetuated ICs• Hypocomplementaemia (C3, C4)

NephropahiesIgA nephropathy• IgA CIC deposition in kidney• Serum IgA, polymers IgA, IgRF

and IgA IC• PDF,TGF-, IL-1 and

IL6mensangial cells

Malaria nephropathy• P.falciparum, P.malaria derived CIC

and deposition• Glomerular deposits – parasite

specific Ags, IgGs, IgM and C components detected

• Profound C3 and C4 hypocomplementaemia

Nephropathy in SchistosomiasisInitiation• Schistosome egg portal, intestinal or

mucosal tracts• T cells primary to persistent SEA• Memory CD4 T cell rechallenge

cytokines (IL-2, -IFN)• Recruitment and activation of

mononuclear phagocyte and polymorphs• Eosinophils MBP, ECP, EPO kidney

tissue direct damage

Granuloma Histology•Eosinophils/granulocytes, epitheliod cells central zone

•Lymphocytes, plasma cells peripheral

Mercury nephropathyTrigger• Mercury containing skin-lightening

creams• GBM – anti GBM IC deposition• GBM damage

Digestive system disordersOral and dental diseases eg• Caries (dental decay); periodontal

disease;Gastroenteropathic conditions eg• Granulomatous colitis (Crohn’s

disease of the colon); malabsorption (coeliac disease); granuloma formation.

Gingivitis and periodontitisPatients infected with gram-negative bacteria eg

Haemophilus species. • Dental caries caused by Streptococcus mutans

infections. • Inflammatory reactions and MAC to mass of

the bacterial adhering onto tooth surface (dental plaque) results in the damage of gingival tissue.

• Toothpaste also contain allergens with adverse effects eg cinnamic aldehyde, cinnamon oil and peppermint

Periodontal diseaseIncreased bacteria growth,

multiplication and its persistence• Ativates T cell functions,

lymphokine production and subsequent exaggerated cellular mechanisms.

• Inflammatory cell recruitment and activation eventually leads to fibrosis in chronic gingivitis.

Periodontal ligament damageIn periodontitis mediated by • MAC• Proteases, prostaglandins,

leukotrienes, PAF, IL-1, TNF and ROI exacerbate damage.

• Further progression associated with exaggerated DTH

Recurrent oral ulcerationRecurrent ulceration of the non-

keratinized oral mucosal membrane.

• Bacterial and viral infection leads to

• Production of agglutinating,• Complement-activating and

cytotoxic antibodies• Mediate oral ulceration and tissue

destruction.

AutoimmunityPersistence of the oral infections

leads to • Generation of autoantibodies• Cross-react with mouth micro-

organisms and oral mucous membrane epithelial cells.

• Autoantibodies exacerbate oral mucosal membrane damage.

Gastroenteropathy disorders• Coeliac disease• Chron’s disease

Coelic diseaseTrigger factors derived from cereals • Mainly wheat, rye, barley or prolamines

eg gliadin, secalin and bordelein, respectively.

• Gluten triggers anti-gliadin IgA and IgG. Immunopathogenesis involves

environmental, genetic and immunological factors

• Coelic disease associated with DR3-DQ2 or DR5/7—DQ2 HLA haplotypes.

Immunopathogenesis contGluten elicits antigen specific Th 1

leading to pro-inflammatory cytokine• Infiltration of IELs into the epithelium

with macrophages leads to inflammatory reaction involving

• Activated mast cells, eosinophils and neutrophils;

• elaboration of cytokines and other products of inflammation.

Increased T cell activityManifestations • Increased T cell activation in the

lamina propria • T cell proliferation in the epithelial

compartment. • IELs, cytolytic T cells exerting

enteropathic effect under the influence of cytokines