Immunodeficiency Disease

1. Introduction 2. Primary immunodeficiency disease 3. Secondary immunodeficiency disease

1. Introduction Immunodeficiency Disease ， IDD ： Integrity of the immune system is essential for defense against infectious agents. Defects in one or more components of the immune system can lead to serious and often fatal disorders.

Mechanism: Mechanism: Abnormalities in different aspects of immune cells, molecules in the development, differentiation, metabolism, regulation. Characteristics: Characteristics: Susceptible, recurrent, refractory, delayed healing, infection of low pathogenicity pathogens. Increased incidence of cancer, autoimmune diseases, allergy. Classification: Classification: Primary IDD, Secondary SIDD specific, non-specific

2. Primary immunodeficiency disease Induction factors: genetic, congenital hypoplastic Age: infant Pathogenesis: Hematopoietic stem cell differentiation and development

Classification:  IDD mainly to humoral immune  IDD mainly to cellular immune  Combined immunodeficiency  Non-specific immune deficiency

1) IDD mainly to humoral immune Feature: Increase the susceptibility of bacteria, intestinal viruses, intestinal parasites, Growth retardation High incidence of autoimmune disease, malignant tumors Reduction in the number of peripheral blood B cells Decrease or absence of the Ig Mechanism: D isorders of B cell differentiation, developmental Th dysfunction

Bruton Disease Selective IgA deficiency X-linked hyperimmunoglobulin M syndrome

Bruton Disease (X-linked agammaglobulinemia) Feature: Lack of B cells and IgG in blood Mechanism: Pre B cell differentiation, developmental disorders Pathogenesis: x-linked recessive, most male Clinical: Repeatedly sustained bacterial infection, no antibody response to vaccination Treatment: Intramuscular injection of gamma globulin

 1  2  AlbuminGlobulin （a） （b） （c）（a） （b） （c） X-linked agammaglobulinemia,

Selective IgA deficiency: common variable Feature: Lack of IgA in serum <50mg/L, sIgA  Mechanism: Final stages of B cell development stagnate Clinical: Recurrent respiratory tract, gastrointestinal tract, urinary tract infection Treatment: Breastfeeding

Endoscopic imaging of the duodenum shows multiple prominent nodules 3–5 mm in size, consistent with nodular lymphoid hyperplasia

X-linked hyperimmunoglobulin M syndrome Feature: With IgM , others  Mechanism: T cell lack of CD40L B cells remain in the IgM stage Antibody type conversion defect Pathogenesis: x-linked recessive, most male Clinlcal: Recurrent pyogenic infections, IgM , IgA, IgG 

2 ) IDD mainly to cellular immune Feature: Increased susceptibility to intracellular bacteria Significantly delayed growth and development, who died in infancy High incidence of malignant tumors Decreased peripheral blood T cells, DTH response to negative, Graft rejection negative. T cell differentiation, developmental disorders

2 ) IDD mainly to cellular immune DiGeorge Syndrome T cell surface molecular structure and function of defect

DiGeorge Syndrome （ Congenital thymic aplasia, III, IV pharyngeal pouch syndrome ） Feature: Absence or hypoplasia of thymus Mechanism: Non-hereditary Pathogenesis: Low cellular immune function, Parathyroid dysfunction Clinical: Repeated intracellular bacteria infection, Graft rejection-free Treatment: Thymus transplantation

Patient with DiGeorge syndrome Depleted thymus-sependent area (TDA) small primary folicles (PF) Normal subject: The populated T-cell area the well-developed secondary folicle with its mantle of small lymphocytes (M) Germinal center (GC)

Nude mice who had no T cells in the thymus is a natural animal model of selective defects

T cell surface molecular structure and function of defect  TCR loss: TCR  CD3 Mutations NF-AT gene defect: reduced immune response IL-2  others

3 ) Combined immunodeficiency Severe combined immunodeficiency disease IDD with enzyme deficiency IDD with other deficiency

Severe Combined Immunodeficiency Disease, SCID Humoral, cellular immune dysfunction at the same time Autosomal recessive SCID Feature: defects in the common stem cells of T, B cell HLA class II molecules defects SCID Clinical: Increased susceptibility to infection, no peripheral blood CD4 + T, B cell function decreased x-sex-linked genetic SCID Mechanism ： IL-2 receptor g chain gene mutation Peripheral blood T, NK cells decreased

A child with severe combined immunodeficiency showing skin lesions due to infection with vaccinia gangrenosum resulting from smallpox immunization. Lesions were widespread over the whole body.

severe combined-immunodeficiency disease, SCID

X-linked SCID, XSCID Mutations in the  c ( common  chain) chain of the receptors for interleukins IL-2, -4,-7,-9 and -15 ** Signal transduction, ** lymphocyte differentiation, proliferation and maturation

4) Non-specific immune deficiency Phagocyte deficiency Feature: Reduction in the number and function of phagocytes defects Clinical: Chronic granulomatous Mechanism: Neutrophil lack of NADH/NADPH oxidase, weakening of oxygen dependent disinfection

Th1 cell 多核巨大细胞 MM 内皮样细胞 xijun 纤维母细胞 Chronic granulomatous

4) Non-specific immune deficiency Complement system deficiency Complement components, regulatory proteins in genetic defects. Hereditary angioedema, lack of C1INH, Vasodilator, capillary permeability, Skin and mucous membrane edema.

3. Secondary immunodeficiency disease 1) SIDD secondary to certain diseases 2) Iatrogenic SIDD 3) Acquired immunodeficiency syndrome

1) SIDD secondary to certain diseases Infection: Virus infection Decreased T cell function Cancer: Significantly decreased of T, B immune function Protein loss: Excessive consumption or insufficient synthesis Ig , Humoral immune function decline Severe malnutrition, Decreased T cell function

2) Iatrogenic SIDD  Long-term use of immunosuppression and certain antibiotics, antitumor drugs  Radiation injury

3) Acquired Immnodeficiency Syndrome, AIDS Etiology: Retroviral RNA HIV HIV-1 HIV-2 infect CD4 + T, M  Glial cells

HIV and AIDS an infectious agent 1979 – 5 cases of Pneumocystis carinii pneumonia With giemsa stain at high magnification, the faint bluish dot-like intracystic bodies of Pneumocystis carinii in lung are seen in this cytologic preparation from a bronchoalveolar lavage Los Angeles only two cases of Pneumocystis carinii pneumonia All homosexuals

HIV Incubation Period (Adults) Not Infected - Infected Infectious AIDS Death years yr-

AIDS Cases by Age and Sex, Reported , United States

Estimated number of AIDS related deaths worldwide WHO

Mother to child transmission of HIV by breast-feeding or other cause WHO

HIV: dsRNA Target cells: immune cells Pathogen:

HIV budding from human lymph tissue (TEM x133,335)

The process of virus invasion into cells A. Attachment B. Endocytosis C. Invasion

The necessity for CD4 antigen expression for entry of HIV into a human cell. HeLa cells do not have CD4 antigen and are not infected. HeLa cells transfected with CD4 gene are infected

Chemokine receptors are involved, in association with CD4 antigen, in infection by HIV (left). The chemokine can block attachment of the virus to its receptors (middle). Mutations in the chemokine receptor can lead to resistence to HIV infection (right)

Virus titer, CD4 and CD8 cell number during the course of HIV infection

Multinucleated cell (syncytium) in touch preparation from cut surface of enlarged lymph node from patient with HIV-1 infection. Cell fusion producing a large multinucleated cell is a viral cytopathic effect characteristic, but not diagnostic, of infection by HIV-1.

Lesions on the stomach of a patient with Kaposi's sarcoma Figure - Kaposi's Sarcoma Kaposi's sarcoma (skin). Skin showing AIDS-associated Kaposi's sarcoma

Scanning electron micrograph of HIV-1 budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions

Clinical manifestations of AIDS

Facial sarcoidosis in AIDS

Hairy leukoplakia of tongue Oral thrush. Orofacial granulomatosis with cobble stone mucosa Candida and herpes simplex Severe angular cheilitis

SUMMARY