PathologyDr. KHALID W. ABDULATTAH
pathology department/Mousel Medical college
Diseases of Immunity (Immunopathology) Lecture 3
Transplant RejectionRejection of organ transplantation is a complex, immunologically mediated, process. It involves hypersensitivity response of the recipient to donor allograft ( which is recognized as a foreign antigen by recipient’s immune system).It results from antigenic differences between recipient and donor tissue in their MHC molecules.
Pathology of Transplant RejectionThere are three types of rejection of renal transplant ( as an example )
Autoimmune DiseasesA number of diseases that are characterized by Immune reactions against self antigens in body tissues.
Tissue damage is mediated by type 2, 3 and 4 hypersensitivity reactions.
The self auto reactivity occurs when the mechanisms of immunological tolerance break down.
Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes
Genetic Factors in Autoimmunity• Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.• Several autoimmune diseases are linked with the HLA locus, especially class II alleles (HLA-DR, -DQ). Role of infection in AutoimmunityAutoantibodies against bacterial antigens may cross react with self antigen sharing similar structure to the micro organism e.g. streptococci and rheumatic heart disease.
The lacrimal and salivary glands characteristically show dense lymphocytic infiltration consisting mainly of activated CD4+ helper T cells and some B cells, including plasma cells.
Serologic studies frequently reveal autoantibodies. Antibodies against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La) , can be detected in as many as 90% of patients by sensitive techniques
IgG4-Related DiseaseIgG4-related disease (IgG4-RD) is a newly recognized constellation of fibro-inflammatory disorders characterized by tissue infiltrates rich in IgG4 antibody-producing plasma cells and lymphocytes, particularly T cells, associated with fibrosis and obliterative phlebitis .
IgG4-related disease has now been described in virtually every organ system.
These include Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands), Riedel thyroiditis, idiopathic retroperitoneal fibrosis, autoimmune pancreatitis, and inflammatory pseudotumors of the orbit, lungs, and kidneys.
The disease most often affects middle-aged and older men.
Immunodeficiency and ImmunosuppressionImmunodeficiency may be
Primary : inherited failure of development of components of immune system
Secondary: due to diseases or their treatment.
Secondary Immunodeficiency:Secondary immunodeficiency are more common than primary, main causes are:
Infection e.g. HIV/AIDS
Patients receiving chemotherapy or radiotherapy for treatment of cancer
Use of immunosuppressive therapy to prevent graft rejection.
HIV/AIDSAIDS is a disease caused by infection with HIV and is characterized by profound immunosuppression with associated opportunistic infections, malignancies, wasting, and central nervous system degeneration.
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 a retrovirus that selectively attacks the CD4 T lymphocytes, the immune cells responsible for orchestrating and coordinating the immune response to infection in addition to macrophages, and dendritic cells.
As a consequence, persons with HIV infection have a deteriorating immune system, and thus are more susceptible to severe infections with ordinarily harmless organisms.
Structure of the human immunodeficiency virus(HIV).• The HIV virion is spherical and containsan electrondense core surrounded by alipid envelope.• The virus core contains the major capsidprotein p24, two copies of the genomicRNA, and three viral enzymes (protease,reverse transcriptase, and integrase).• Because p24 is the most readilydetected antigen, it is the target for theantibodies used in screening for HIVinfection.• The viral core is surrounded by a matrixprotein called p17, which lies beneaththe viral envelope.• The viral envelope is studded with twoviral glycoproteins, gp120 and gp41,which are critical for the infection ofcells.
Stages of HIV InfectionThe typical course of HIV infection is defined by three phases,
which usually occur over a period of 8 to 12 years. The three phases
1- the primary infection phase.
2- chronic asymptomatic or latency phase.
3- overt AIDS phase
the primary infection phase (stage 1) may include fever, fatigue , myalgias, sore throat, night sweats, gastrointestinal problems, lymphadenopathy, maculopapular rash, and headache.
Stages of HIV InfectionThe primary stage is followed by a latent period (stage 2) during which the person has no signs or symptoms of illness. The median time of the latent period is about 10 years. During this time, the CD4 T-cell count falls gradually from the normal range of 800 to 1000 cells/L to 200 to 400 cells/L (14% to 28%). Lymphadenopathy develops in some persons with HIV infection during this phase.
The third phase (stage 3), overt AIDS, occurs when a person has a CD4 T-cell count of less than 200 cells/L (14%) or an AIDS-defining illness. Without antiretroviral therapy, this phase can lead to death within 2 to 3 years. The risk of opportunistic infections and death increases significantly when the CD4+ T-cell count falls below 200 cells/L.
Mode of transmission of HIV infectionSexual 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.
Pathological features of HIV/AIDSThey are non specific ( except for CNS infection) and are mainly due to opportunistic infections, Kaposi sarcoma and other tumors
Cytomegalovirus 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.
Mycobacterial infections do not lead to granuloma formation because CD4+ T lymphocytes are lacking but only accumulation of unactivated macrophages engulfing mycobacteria.
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.
"Three M’s of herpes simplex virus" - margination of nuclei, molding and multi nucleationWith intranuclear eosinophilic amorphous or droplet - like bodies surrounded by a clear halo
Pneumocystis jiroveciis a fungus that only causes disease in immunosuppressed patients due to HIV infection or transplantation. It spreads by droplet infection leading to pneumonia.
Microscopically, the typical case is characterized by a foamy or honeycombed intra-alveolar exudate accompanied by a lymphoplasmacytic interstitial infiltrate preventing gas exchange.
The diagnosis is made by identifying the organism in sputum or bronchial lavage specimens or by lung biopsy.
CNS involvement in patient with AIDSIs an important AIDS-defining feature involving 90% of patients and include
Opportunistic infections of brain and meninges e.g. Toxoplasmosis, cryptococcosis.
JC virus causes progressive multifocal leukoencephalopathy
Primary B-cell lymphoma of brain
AIDS-Dementia complex: is a late feature due to cerebral atrophy and HIV-encephalitis (HIV infection of brain tissue).
Cerebral toxoplasmosis with hemorrhagic necrotic lesion compressing brain tissueHIV-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.
AmyloidosisAbnormal deposition of amyloid protein extracellularly in various tissues of the body.
Classification of Amyloidosis and Mechanisms ofAmyloid FormationAmyloidosis results from abnormal folding of proteins, which assume a β pleated sheet conformation, aggregate, and deposit as fibrils in extracellular tissues. The proteins that form amyloid fall into two general categories: Normal proteins that have an inherent tendency to associate and form fibrils, particularly when produced in increased amounts; and(2) mutant proteins that are prone to misfolding and aggregation.
Structure of amyloid:Amyloid protein is a fibrillar protein. Three 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.β-amyloid protein (Aβ) is a peptide that is derived by proteolysis from a much larger transmembrane glycoprotein, called amyloid precursor protein.
Pathology of Amyloidosis: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
Amyloidosis of kidney-congo red stainAmyloidosis of kidney- polarized light, the Congo red stained amyloid shows apple-green birefringence.
The diagnosis of amyloidosis depends on the histologic demonstration of amyloid deposits in tissues.
The most common sites biopsied are the kidney, when renal manifestations are present, or rectal or gingival tissues in patients suspected of having systemic amyloidosis.
The prognosis for individuals with generalized amyloidosis is poor.
Those with AL amyloidosis (not including multiple myeloma) have a median survival of 2 years after diagnosis.
Individuals with myeloma-associated amyloidosis have an even poorer prognosis.
The outlook for individuals with reactive systemic amyloidosis is somewhat better and depends to some extent on the control of the underlying condition.