Immunopathology

Diseases of Immunity (Immunopathology)

Immunodeficiency and Immunosuppression Immunodeficiency may be Primary : inherited failure of development of components of immune system Secondary: due to diseases or their treatment.

Primary Immunodeficiency Are rare life threatening disorders X linked Agammaglobulinemia Failure of B cell maturation with mutation in genes responsible for light chain production, this leads to defective production of all types of immunoglobulin (defective humoral immunity). Once maternal antibodies decrease in blood, the child becomes susceptible to recurrent bacterial infections.


Di George syndrome (Thymic hypoplasia) Failure of development of thymus from bronchial arches due to chromosomal deletion, so there is no suitable environment for T cell maturation. The patient is susceptible to infections by viruses, fungi , parasites and by mycobacteia ( defective cell mediated immunity).


Secondary Immunodeficiency: Secondary immunodeficiency are more common than primary, main causes are: Malnutrition Infection e.g. HIV/AIDS Cancer Renal diseases Patients receiving chemotherapy or radiotherapy for treatment of cancer Use of immunosuppressive therapy to prevent graft rejection.

HIV/AIDS

AIDS is a disease characterized by profound immunosuppression which leads to opportunistic infections, secondary neoplasms and neurological disorders. The virus causing AIDS is human immunodeficiency virus (HIV) of which type I (HIV-1) is globally distributed and the second type (HIV-2) is restricted to African countries.

HIV is RNA retrovirus belonging to the lentivirus family, HIV viron has a spherical shape containing a central core surrounded by a lipid envelope derived from host cell membrane. The core consists of: Two copies of viral RNS surrounded by (2) matrix protein surrounded by


(3) viral envelope which has surface glycoprotein receptors called gp120 and gp41 which bind to CD4 receptors on the surface of CD4+ T lymphocytes, macrophages and dendritic cells and facilitate the entry of the virus into these cells and are critical for HIV infection.CD4 receptors have high affinity for HIV that is why HIV virus has a selective tropism for CD4+ cells.


Pathogenesis: HIV enters a susceptible mucosal langerhans’ dendritic cells (antigen presenting cell) through CD4 receptors, these cells present the virus to CD4 +T lymphocytes. A CD4+ cell fuses with dendritic cell and become infected ( also by binding of gp120 of virus with CD4 receptors of T lymphocyte).


The infected CD4+ T lymphocytes then pass to the regional lymph nodes where they activate and infect more CD4+ T lymphocytes and macrophages ( through the same receptor binding). CD4 receptors are also present on the surface of macrophages therefore through this way microglia (brain macrophages) become infected and infection spread to the brain and lungs. In infections transmitted by blood, HIV viron directly infect CD4+ cells without need of dendritic cells.

Once HIV enters CD4+ T lymphocytes, the RNA of the virus is transcribed into DNA and become integrated into the DNA of the dividing host cell. The virus remains in host cells for years ( latent infection) , later one; replication of the virus leads to productive infection, viral budding from the cell and cell death, this leads to loss of CD4+ T lymphocytes from peripheral blood and profound immunosuppression.

During the latent phase of infection, HIV colonizes lymphoid tissues (spleen, lymph nodes, tonsils) and infect T cells, macrophages and dendritic cells ( but not peripheral blood lymphocytes). These cells act as reservoir of infection, the patient is asymptomatic but is highly infectious during this period (initially the immune system vigorously proliferate to replace the dying T cells thus masking cell death in the lymphoid tissues).

During the productive phase, all T cells (including peripheral T cell) are destroyed leading to profound immunosuppression and development of opportunistic diseases indicating a state of severe cellular immunosuppression.

Mode of transmission of HIV infection

Sexual transmission: Accounts for greater than 75% of all cases of HIV transmission through both heterosexual and homosexual intercourse. The virus is present in semen both extracellularly and within mononuclear inflammatory cells and enters the recipient body through tears and abrasions in the mucosa.


Sexual transmission of HIV is facilitated in the presence of other sexually transmitted diseases causing genital ulcerations, because these concomitant infections increase the contents of inflammatory cells in seminal and cervical secretions.

2. Parenteral transmission: Intravenous drug abusers through sharing needles and syringes contaminated with HIV-containing blood. Blood transfusion and infected blood products e.g. Factor VIII concentrate for hemophilic patients. Accidental percutaneous injury with infected blood e.g. health care workers.


AIDS-Defining Opportunistic Infections and Neoplasms Found in Patient with HIV-Infection: Viral infections Cytomegalovirus (pulmonary, intestinal, retinitis, CNS infection) Herpes virus (localized or disseminated) Bacterial infections Mycobacterium tuberculosis (pulmonary and disseminated infection) Mycobacterium avium


Streptococcus pneumoniae (pneumonia) Non-typhoid Salmonella infection (enteritis, disseminated infection) Treponema pallidum (Syphlis) Fungal infections Pneumocystis carini (pneumonia, disseminated infection) Candida albicans ( esophageal,tracheal,pulmonary infections) Cryptococcus neoformans (pneumonia, CNS infection)

Protozoal infectionsLeishmania species ( cutaneous or disseminated infections)Toxoplasma gondii (pneumonia or CNS infection)HIV-associated tumorsKaposi’s sarcomaNon-hodgkin lymphoma: cerebral and extra cerebral (Burkitt lymphoma)Mucosal squamous cell carcinomas:cervix, anus, conjunctiva.

Other HIV-associated diseases Central nervous system: HIV encephalitis and dementia. Gut: mucosal HIV infection and malfunction Kidney: HIV-associated nephropathy.

Pathological features of HIV/AIDSThey are non specific ( except for CNS infection) and are mainly due to opportunistic infections, Kaposi’s sarcoma and other tumorsCytomegalovirus is acquired by transplacental way and causes pneumonia, intestinal lesion and CNS infections. It is diagnosed by finding viral inclusions in biopsies.Herpes simplex virus is transmitted by direct contact with infected lesion mainly from sexual intercourse causing painful genital ulcerations. Epithelial cells sheded from the ulcer show nuclear inclusions of the virus.

This is cytomegalovirus (CMV) infection in the lung. Note the very large cells that have large violet intranuclear inclusions with a small clear halo. Basophilic stippling can be seen in the cytoplasm.


Mycobacterial infections do not lead to granuloma formation because CD4+ T lymphocytes are lacking but only accumulation of unactivated macrophages engulfing mycobacteria. Pneumocystis carinii is a fungus that only causes disease in immunosuppressed patients due to HIV infection or transplantation. It spreads by droplet infection leading to pneumonia, the alveoli are filled with masses of cysts containing small nuclei and preventing gas exchange. The diagnosis is made by identifying the organism in sputum or bronchial lavage specimens or by lung biopsy.

Pneumocystis carinii pneumonia: alveoli are filled with numerous cysts

HIV-Associated tumorsKaposi’s sarcoma: is a rare vascular tumor but the most common neoplasm in AIDS patients. It has recently been established that this tumor is due to a virus transmitted sexually called human herpes simples virus 8 and HIV stimulates further proliferation of spindle cells leading to Kaposi’s sarcoma. The tumor affects skin, lymph nodes and internal organs and appears grossly as infiltrative red nodules.Microscopically: spindle shaped cells with RBCs between tumor cells.

Kaposi sarcoma : atypical spindle cells enclosing slit like vascular spaces this otherwise rare tumour is a frequent finding in patient with AIDS.



Cerebral toxoplasmosis with hemorrhagic necrotic lesion compressing brain tissue

Amyloidosis

Abnormal deposition of amyloid protein extracellularly in various tissues of the body.

Structure of amyloid: Amyloid protein is a fibrillar protein. Two main types of this protein are present: Amyloid light chain (AL) is derived from plasma cells and consists of immunoglobulin light chain produced by proliferating B-cell tumors. Amyloid-Associated (AA) protein: is high molecular weight protein that does not contain immunoglobulin in its structure. It is synthesized in the liver and associated with chronic inflammatory diseases.

Classification of Amyloidosis: Generalized (systemic) amyloidosis: involving several organs. Localized amyloidosis: amyloid deposits are limited to a single organ. Hereditary amyloidosis

Systemic amyloidosis is further sub classified into: A) Primary Amyloidosis : due to blood dyscrasia e.g. multiple myeloma ( a malignant tumor of plasma cells). The amyloid deposition is systemic and of AL type. Malignant plasma cells secrete excessive amount of immunoglobulin light chains called Bence Jones protein which is also present in serum and urine.

B) Reactive (secondary) systemic Amyloidosis: amyloid deposits involve multiple organs but of AA type. It is due: 1) Infections e.g. T.B. 2) Non infectious chronic inflammatory processes : Bronchiactasis Chronic osteomylitis Rheumatoid arthritis Inflammatory bowel diseases

It is possible that chronic inflammation causes activation of macrophages resulting in secretion of IL-1 and 6 which stimulate liver cells to serum amyloid associated protein which form AA protein of amyloidosis. C) Senile systemic amyloidosis in elderly.

Localized amyloidosis Amyloid deposits are limited to a single organ or tissue without involvement of any other site producing localized nodular mass e.g. lung, larynx, skin, tongue .etc. amyloid deposit is of AL type, some of these localized lesions are due to endocrine tumors ( endocrine amyloid) like medullary carcinoma of thyroid and carcinoma of stomach.

Pathology of Amyloidosis: Grossly: Amyloid may or may not be apparent grossly and is recognized after painting the cut surface of the organ with iodine. Amyloid deposits stain brown with iodine. Large amount of amyloid causes enlargement of the organ and tissue appears gray with waxy firm consistency .

Macroscopically the affected organ(lymph node ) is enlarged, firm & has waxy consistency

Histologically: the deposition of amyloid is always between cells (extracellular) with the usual hematoxylin and eosin stain, amyloid appears as an amorphous, eosinophilic hyaline extracellular substance producing pressure atrophy of adjacent cells.

The most commonly used special stain for amyloid is Congo red (which differentiates amyloid from other H&E similar materials like hyaline,fibrin). Under light microscope, with Congo red stain, amyloid appears red but under polarized light, the Congo red stained amyloid shows apple-green birefringence. Amyloid fibrils can be defined with electron microscope.


By H&E the amyloid appears as an amprphous, eosinophilic hyaline extracellular substance that with progressive accumulation lead to pressure atrophy of adjacent cells


In the kidney the amyloid is deposited primarily in the glomeruli, interstitial peritubular tissue, arteries & arterioles.

Amyloidosis of kidney-congo red stain

Amyloidosis of kidney- polarized light, the Congo red stained amyloid shows apple-green birefringence.


Amyliod tissue appears as acellular, amorphous, eosinophilic infiltrate within the lymph node.

Amyloid deposits stain orange-red with Congo Red stain

With Congo Red stain, amyloid deposits produce characteristic apple-green birefringence under polarized light.

A section of liver stained with congo red reveals pink-red deposits of amyloid in the wall of blood vessels & along the sinusoids
Note the yellow green birefringence of the deposits when observed by polarizing microscope