Define hypersensitivity reaction. What are the different types of hypersensitivity reaction and suggest an example each of one of them. Discuss briefly the mechanisms of pathogenesis of “Erythroblastosis fetalis” – a hemolytic disease of the newborn. How will you prevent and control this condition

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Hypersensitivity reaction

A hypersensitivity reaction is an excessive, inappropriate, or harmful immune response occurring in a previously sensitized individual, resulting in tissue injury when the person is exposed again to the antigen.

Robbins & Kumar Basic Pathology, p. 141

Types of hypersensitivity reactions

Type	Main immune mechanism	Typical onset	Example
Type I - Immediate (anaphylactic)	Allergen-specific IgE bound to mast cells. Re-exposure causes mast-cell degranulation and release of histamine and other mediators.	Minutes	Anaphylaxis after penicillin, allergic rhinitis, bronchial asthma
Type II - Antibody-mediated (cytotoxic)	IgG or IgM reacts with antigens on cell surfaces or extracellular matrix. Injury occurs through complement activation, opsonization/phagocytosis, or antibody-dependent cellular cytotoxicity.	Hours to days	Mismatched blood transfusion, autoimmune hemolytic anemia, erythroblastosis fetalis
Type III - Immune-complex mediated	Circulating antigen-antibody complexes deposit in tissues, activate complement, and attract neutrophils, causing inflammation.	Hours to days	Serum sickness, Arthus reaction, systemic lupus erythematosus
Type IV - Delayed-type, T-cell mediated	Sensitized T lymphocytes cause cytokine-mediated inflammation or direct cytotoxicity. Antibodies are not involved.	48-72 hours	Tuberculin skin test, contact dermatitis due to nickel, graft rejection

Robbins & Kumar Basic Pathology, pp. 141-149; Roitt's Essential Immunology, pp. 407-426.

Erythroblastosis fetalis

Erythroblastosis fetalis, also called hemolytic disease of the fetus and newborn (HDFN), is a form of type II hypersensitivity reaction in which maternal IgG antibodies destroy fetal red blood cells.

The classical and most important form results from Rh(D) incompatibility:

Mother: Rh-negative
Father: Rh-positive
Fetus: may be Rh-positive

Other antibodies, including those against Kell, c, E, Duffy, and sometimes ABO antigens, can also cause HDFN. However, Rh(D) disease is the classical examination example.

Pathogenesis

1. Sensitization of the Rh-negative mother

During the first pregnancy with an Rh-positive fetus, a small quantity of fetal Rh-positive red cells may enter the maternal blood, particularly:

At delivery
During abortion, miscarriage, ectopic pregnancy
Following antepartum hemorrhage or abdominal trauma
After invasive procedures, such as amniocentesis
Following incompatible Rh-positive blood transfusion

The fetal Rh(D) antigen stimulates the Rh-negative mother to produce anti-D antibodies. The initial response is often mainly IgM, which does not cross the placenta. Therefore, the first Rh-positive fetus is usually unaffected or only mildly affected.

2. Formation of maternal anti-D IgG and memory cells

Maternal B cells undergo class switching and form IgG anti-D antibodies and memory B cells. In a later Rh-positive pregnancy, the mother mounts a rapid, stronger secondary immune response with high-titer anti-D IgG.

3. Transplacental transfer of IgG

Maternal anti-D IgG crosses the placenta, especially later in pregnancy, and attaches to Rh(D)-positive fetal red cells.

4. Fetal hemolysis

The antibody-coated fetal erythrocytes are removed mainly by macrophages in the fetal spleen and liver. This results in:

Hemolytic anemia
Increased erythropoiesis
Release of immature nucleated red cells, or erythroblasts, into fetal blood, hence the name erythroblastosis fetalis
Hepatosplenomegaly due to extramedullary hematopoiesis
High-output cardiac failure
Generalized edema and hydrops fetalis
In severe cases, intrauterine death or stillbirth

After birth, placental removal stops bilirubin clearance by the mother. Continued hemolysis can produce severe unconjugated hyperbilirubinemia, jaundice, and kernicterus.

Robbins & Kumar Basic Pathology, p. 141; Katzung's Basic and Clinical Pharmacology, 16th ed., p. 1535; Ganong's Review of Medical Physiology, 26th ed., chapter “Hemolytic Disease of the Newborn.”

Prevention

1. Antenatal blood grouping and antibody screening

At the first antenatal visit:

Determine maternal ABO and Rh(D) blood group.
Screen maternal serum for clinically significant red-cell antibodies using the indirect Coombs test.
Repeat antibody screening later in pregnancy according to local protocol.

An Rh-negative woman who already has immune anti-D antibodies cannot be protected by anti-D prophylaxis and needs specialist fetal surveillance.

2. Anti-D immunoglobulin prophylaxis

Give anti-D immunoglobulin to an unsensitized Rh-negative mother carrying, or potentially carrying, an Rh-positive fetus.

It is given:

Routinely during late pregnancy, commonly at about 28 weeks or through a local routine antenatal anti-D prophylaxis regimen.
Within 72 hours after delivery of an Rh-positive infant.
After any potentially sensitizing event, such as miscarriage, induced abortion, ectopic pregnancy, antepartum hemorrhage, abdominal trauma, external cephalic version, or invasive prenatal procedure.

Anti-D immunoglobulin binds Rh-positive fetal red cells in maternal circulation and promotes their clearance before the mother can mount her own immune response. Thus, maternal anti-D memory B cells do not develop.

The textbook describes administration within 24-72 hours after birth, and a common preparation as 300 micrograms intramuscularly; exact product, dose, and event-specific indications should follow the local obstetric/transfusion protocol. Katzung's Basic and Clinical Pharmacology, 16th ed., p. 1535. The British Society for Haematology anti-D guidance supports routine antenatal and postpartum prophylaxis for eligible non-sensitized RhD-negative women.

3. Avoid sensitizing transfusions

An Rh-negative girl or woman of child-bearing potential should receive Rh-negative blood whenever possible, unless an emergency protocol requires otherwise.

Control and treatment of an affected pregnancy or newborn

If the mother is already alloimmunized:

Assess antibody level and fetal risk by serial maternal antibody titers and paternal/fetal Rh typing where available.
Monitor fetal anemia, commonly with middle cerebral artery Doppler assessment.
Treat severe fetal anemia with specialist-guided intrauterine transfusion and plan delivery at an appropriate gestation.
Treat the newborn with monitoring of hemoglobin and bilirubin, phototherapy, intravenous immunoglobulin in selected cases, and exchange transfusion when severe hemolysis or hyperbilirubinemia warrants it.
Provide compatible antigen-negative blood for fetal or neonatal transfusion.

Recent reviews continue to support prevention of alloimmunization through anti-D prophylaxis; no recent evidence identified here changes this core approach. Relevant recent reviews include PMIDs 39116441, 40728267, and 41406924.

Explain why infective endocarditis commonly affects previously damaged heart valves.

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infective endocarditis pathogenesis damaged heart valve endothelial injury platelet fibrin vegetation

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Infective endocarditis commonly affects previously damaged valves because injury creates a surface on which microbes can attach and multiply.

Mechanism

Abnormal valves cause turbulent blood flow
Conditions such as rheumatic valvular disease, mitral valve prolapse, bicuspid aortic valve, calcific stenosis, congenital defects, and prosthetic valves alter normal flow. High-velocity jets traumatize the valvular endothelium.
Endothelial injury exposes a thrombogenic surface
The damaged endocardium promotes deposition of platelets and fibrin, producing small sterile thrombi called nonbacterial thrombotic vegetations.
Transient bacteremia seeds these deposits
Bacteria entering the bloodstream, for example after dental infection or procedures, skin infection, intravenous drug use, or invasive devices, can adhere to the platelet-fibrin deposits. Less virulent organisms such as viridans streptococci particularly need this damaged surface for colonization.
Vegetations protect bacteria
Organisms become embedded in layers of fibrin and platelets. This relatively avascular environment limits access of phagocytes, antibodies, complement, and antibiotics. The organisms proliferate and form the characteristic infected vegetation.
Progressive valve destruction follows
The vegetation may erode or perforate valve leaflets, cause regurgitation, form abscesses, and embolize.

Thus, damaged valves provide both a nidus for bacterial adherence and a protective platelet-fibrin environment that permits bacterial growth.

Important exception: highly virulent organisms, especially Staphylococcus aureus, can infect even previously normal valves and usually cause acute endocarditis.

Robbins & Kumar Basic Pathology, pp. 367-368.

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