Reproductive and Urinary system disorders

• Foetal Accept ance Mec han isms • Reproducti ve sys tem di sorders • Uri nary system disordes

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

De cidua Ph ysi cal Ba rrier Zygote sequestered in decidua
Decidua provides

• Specialized gestation tissue formed by trophoblast invasion of the uterine tissue. • Physical or anatomical barrier for foetus • Prevents release of foetal and trophoblast antigens into lymphatic vessels.  

Trophoblas t-deriv ed factor s

Normal 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.

Pr ivile ged Sit es
• 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)

Expression 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.

Privileged sites cont

Th 1/Th 2 Re sp onse s
Th2 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 expressi on • 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 Expression

Paternal 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.

Immunosuppressive factors

• 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

Consequences of Lack of HLA-G

• Inadequate blocking antibody formation • Ineffective camouflage of placenta • Placenta cells failure to grow and divide • Death of placenta cells

Phospholipid molecules include

Pho sphol ipi ds

• Cardiolipin ethanolamine, • Glycerol, inositol, phosphatic and serine with • Important function in cell membranes and intracellular organelles
Serine 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

Syn cytio trophoblast
• • • • Feeds the baby Produces β- hCG and progesterone Grows throughout pregnancy Delayed formation of syncytiotrophoblast leads to pregnancy loss or implantation failure

Autoantibody to DNA leads to

Auto imm une R esponses

• 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

Women with infertility, implantation failures and recurrent pregnancy losses

Antisperm antibodies

• Have anti-sperm antibodies associated with antiphospholipid antibodies

Antisperm antibodies inactivate sperms resulting in • Couples unable to conceive normally and multiple failed pregnancies

Anti bodi es 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

Anti bodi es to Neurotransmi tt ers Antibodies 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

Pr egnancy In duced Im mu nosu ppressio n • 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).

MA LE IN FERTI LITY
• Anti-sperm antibodies and autoantibodies ↑ • B and T lymphocytes in semen • Granulocytes and mφ in ejaculates

ABO incompati bil ity • IgM isoagglutinins against ABO antigens (allogeneic blood transfusions) IgG • Agglutination, C1 activation and intravascular haemolysis, circulatory shock

HAEM OL YTIC DIS EASE OF NE WBO RN

Rh in compatibility
• 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)

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

GLO MERO LO NEPH RITI S (GN)

Neutrophil-mediated damage
• Augmented by platelets • Mφ produce proinflammatory substances • Prostaglandins, leukotrienes, TNF-α and polypeptide growth factors

• Streptococcal-antistreptoccal IC deposition in kidney • Autoantibodies against C3bBP complex↑
• Cause membrane proliferative GN type 1 tissues

Post -str eptococcal nephri tis

• Autoimmunity perpetuated ICs • Hypocomplementaemia (C3, C4↓)

Ig A nephropat hy • IgA CIC deposition in kidney • Serum IgA, polymers IgA, IgRF and IgA IC↑ • PDF,TGF-β, IL-1 and IL6→ mensangial cells

Nephropahies

Ma la ria n ephropathy
• P.falciparum, P.malaria derived CIC and deposition • Glomerular deposits – parasite specific Ags, IgGs, IgM and C components detected • Profound C3 and C4 hypocomplementaemia

In it iation • Schistosome egg → portal, intestinal or mucosal tracts • T cells primary to persistent SEA • Memory CD4 T cell rechallenge → cytokines (IL-2, γ-IFN) • Recruitment and activation of mononuclear phagocyte and polymorphs • Eosinophils → MBP, ECP, EPO → kidney tissue direct damage

Nephropathy in Schistosomiasis

Granul om a Histol ogy

• Eosinophils/granulocyt es, epitheliod cells → central zone • Lymphocytes, plasma cells peripheral

Me rcury nephropathy
Trigger • Mercury containing skinlightening creams • GBM – anti GBM IC↓ deposition • GBM damage

Digestive system disorders
Oral 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.

Patients 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

Gingivitis and periodontitis

Increased 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.

Pe rio dontal d isease

In periodontitis mediated by • MAC • Proteases, prostaglandins, leukotrienes, PAF, IL-1, TNF and ROI exacerbate damage. • Further progression associated with exaggerated DTH

Periodontal ligament damage

Recurr ent oral ul cerati ulceration of the nonon Recurrent
• • • • keratinized oral mucosal membrane. Bacterial and viral infection leads to Production of agglutinating, Complement-activating and cytotoxic antibodies Mediate oral ulceration and tissue destruction.

Autoimmunity

Persistence of the oral infections leads to • Generation of autoantibodies • Cross-react with mouth microorganisms and oral mucous membrane epithelial cells. • Autoantibodies exacerbate oral mucosal membrane damage.

Gastroenteropathy disorders
• Coeliac disease • Chron’s disease

Coelic disease

Trigger 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 DR3DQ2 or DR5/7—DQ2 HLA haplotypes.

Immunopathogenesis cont

Gluten 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.

Manifestations • 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

Increased T cell activity

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