Immunology and Immunopathology

GENERAL FEATURES OF IMMUNE RESPONSES
Organization, operating principles and functions of the immune system. Distinctive features of innate and adaptive immune responses. Organs, tissues, humoral and cellular components of the innate and adaptive immune systems. Role of innate immunity in the activation of adaptive immunity. The phases of the immune response (recognition, activation, effector phase).

INNATE IMMUNITY
Recognition of structural motifs
Recognition of pathogens and danger signals by innate immune cells: pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), Toll-like receptors and other pattern recognition receptors (PRR).
Complement system
Complement proteins and activation cascade by classical, alternative, and lectinic pathways. Structure and mechanism of action of the membrane attachment complex. Mechanisms of regulation of complement activation. Biological functions of complement: cytolysis, opsonization, production of anaphylotoxins, solubilization and elimination of immune complexes. Role of complement in the inflammatory response.
Cytokines
General properties of cytokines. Structure and function of cytokines and their receptors.
Natural killer cells (NK)
Recognition of the target cell and the missing-self hypothesis. Activator receptors and inhibitory receptors. KIR (killer Ig-like receptors), NCR (natural cytotoxicity receptors) and lectin-type receptors. Cytotoxic mechanisms of NK cells. Cell-mediated antibody-dependent cytotoxicity (ADCC). Other biological activities of NK cells.

ADAPTIVE IMMUNITY
Organization and development of the adaptive immune system
Central organs: Ontogenesis of lymphocytes. Structure of the bone marrow and thymus. Function of the bone marrow and thymic microenvironments in the proliferation and development of lymphocytes, in the generation of the immune repertoire and in the induction of central tolerance. Thymic involution. Peripheral organs: Structure of the lymph nodes, the white pulp of the spleen and the lymphatic system at the epithelial barriers. Function of peripheral organs as sites of immune responses. Distribution of lymphocytes in the blood, lymph and lymphatic organs; distinction between T-dependent and B-dependent areas. Function and principles of lymphocyte recirculation; migration of lymphocytes in lymphatic and non-lymphatic tissues and role of adhesion molecules. Organization of the immune system at the epithelial barriers.
Antigens (Ags)
Definition of Ag, immunogen, antigenic determinant or epitope, vector, hapten. Properties of linear, conformational, and neoantigenic Ags. Physico-chemical properties of epitopes for B lymphocytes and T lymphocytes. Binding of peptides to the peptide-binding groove of class I and II MHC molecules; role of MHC polymorphism in epitope selection. Immunodominant epitopes. Agonist and antagonist epitopes. Polyclonal activators and superantigens.
Immunoglobulins (Igs) and generation of the variability of their repertoire
Functions of Igs as soluble molecules (antibodies) and as membrane receptors for the antigen. Ig structure: heavy and light chains; immunoglobulin domains; domains of constant and variable regions; hypervariable regions; binding site. Antigenic determinants of Igs: isotypes, allotypes and idiotypes. Molecular features and biological properties of the classes and subclasses of Igs. Structural differences between membrane Igs and soluble Igs. Molecular basis of the generation of the antibody repertoire: organization of light and heavy chain genes; mechanisms of rearrangement of the genes of the variable region. Molecular basis of class switching, co-expression of IgM and IgD, production of membrane and soluble Igs. Molecular basis of affinity maturation.
Antigen-antibody reaction
Physico-chemical basis of the binding between antigen and antibody. Principles of precipitation, agglutination and neutralization reactions. Antibody titer. Examples of immunological techniques applied to medicine: precipitation reactions and immunoelectrophoresis; agglutination reactions in the serological diagnosis of infectious diseases; passive or conditioned agglutination; complement deviation reaction. Immunofluorescence techniques. Principles of flow cytometry and diagnostic applications.
Monoclonal antibodies
Principles of hybridoma production techniques by cell fusion. Chimeric antibodies, humanized antibodies. Use of monoclonal antibodies in diagnostics, therapy, research.
B lymphocytes: development, selection, activation
Structure of the B cell receptor (BCR) complex. Maturation of B lymphocytes. Conventional and unconventional B cell subsets. Early biochemical phenomena induced by antigen recognition through BCR. Activation, proliferation and differentiation of B lymphocytes. Responses to thymus-dependent antigens: collaboration between T helper lymphocytes and B lymphocytes; structure and function of the germinal centers; class switching, maturation of affinity, immunological memory; kinetics of primary and secondary responses. Responses to thymus-independent antigens.
Molecules of the Major Histocompatibility Complex (MHC)
Organization of MHC genes and their inheritance. Polymorphism and multiallelism. Structure and function of class I and class II MHC molecules. Cellular distribution of MHC molecules.
Antigen processing and presentation to T lymphocytes
Professional and non-professional antigen-presenting cells (APC). Endogenous (proteasomal) and exogenous (lysosomal) pathways of Ag processing. Co-presentation and cross-priming.
T lymphocytes: development, selection, activation
Alpha-beta and gamma-delta T cell receptor (TCR). TCR structure: alpha, beta, gamma and delta chains; variable and constant regions; hypervariable regions; Ag-binding site. Molecular basis of the generation of the variability of the TCR repertoire: organization of the genes of alpha, beta, gamma and delta chains; mechanisms of rearrangement of the genes of the variable region. Structure of the TCR receptor complex. Structure and function of the accessory molecules CD4 and CD8. MHC restriction. Early biochemical phenomena induced by the Ag recognition through the TCR. Maturation and maturation stages of T lymphocytes in the thymus. Positive and negative selection. Subsets of T lymphocytes and their activation: T helper (Th) lymphocytes: cellular interactions, adhesion and costimulation molecules, and cytokines involved in the activation of Th cells. Factors that regulate the differentiation of Th0 towards the functional subtypes Th1, Th2, Th9, Th17, Th22, Tregs. Immune functions ofdifferent TH cell subsets. Th1/Th2 balance. Naive, central memory, effector memory T cells. Secondary responses. Cytotoxic T lymphocytes (CTLs): cellular interactions, adhesion and costimulation molecules, and mechanisms involved in the activation of CTLs. Distinctive features of pre-CTLs and CTLs. Steps in the killing of the target by the CTLs: recognition, attack, removal. Mechanisms of cytoxicity and involved molecules. Naive, central memory, effector memory T cells. Regulatory T lymphocytes (Tregs): Distinctive features between natural Tregs and inducible Tregs. Origin, immunophenotype and function of different subsets of Tregs, and their mechanisms of action.
Immune tolerance
Definition of immune tolerance. Tolerance induction to foreign Ags. Natural tolerance to self Ags. Tolerance of T and B lymphocytes. Mechanisms of central and peripheral tolerance. Role of Tregs and NKT cells in controlling peripheral tolerance.

THE PROTECTIVE ROLE OF THE IMMUNE SYSTEM
The immune system against infectious agents
Role of dendritic cells in the activation and polarization of primary responses against different types of microorganisms. Role of the effector functions of innate, adaptive, humoral and cell-mediated immunity, in the defense against bacteria, viruses, fungi, parasites. Role of the transplacental passage of IgGs and the intake of IgAs with breast milk in the defenses of the newborn. The role of vaccinations in anti-microbial defenses. Active and passive immunization.
Transplantation immunology
Molecular and cellular basis of allogeneic recognition. Mixed leukocyte culture reaction (MLR) and activation of alloreactive T lymphocytes. Mechanisms of hyperacute, acute, chronic rejection. Main organ transplants in clinical practice. Haploidentical transplant. Principles of HLA typing techniques. Graft Versus Host Disease (GVHD) reaction. Transfusions of blood components and transfusion reactions. Immunity and pregnancy: the fetus as an allograft.
Tumor immunology
Tumor antigens. Effective mechanisms of immunity against tumors. Role of inflammation in the development and progression of tumors. Mechanisms of tumor immune escape. Immunosurveillance and cancer immunoediting. Diagnostic-prognostic use of tumor antigens and tumor markers. Principles of cancer immunotherapy.

IMMUNOPATHOLOGY
Hypersensitivity reactions
Definition and classification of hypersensitivity reactions according to Gell and Coombs classification of the immunopathological mechanisms involved in immediate, intermediate, and delayed-type hypersensitivity reactions. Sensitization phase and trigger phase. Classification of the most common allergens based on the route of entry into the body. Principles of immunological diagnosis in vivo and in vitro. Principles of antigen-specific immunotherapy.
Autoimmunity and autoimmune diseases
Multifactorial pathogenesis of autoimmune diseases. Mechanisms of loss of tolerance to self Ags. Systemic and organ-specific autoimmune diseases. Humoral and cell-mediated immunopathological mechanisms of the most common autoimmune diseases.
Immunodeficiency syndromes
Congenital and acquired immunodeficiency syndromes. Immunodeficiencies due to Ig deficiency; deficiency of T, B or combined lymphocytes; phagocyte deficiency; deficiency of complement components. Acquired Immunodeficiency Syndrome (AIDS).
Immunosenescence
Definition of immunosenescence. Impact of aging on the different components of the immune system. Role of chronic inflammation in immunosenescence processes. Impact of immunosenescence on health and disease.