Autoimmunity and Immunodeficiencies Lecture 15 PDF

Immunology II BMS44210A Dr. Afsheen Raza [email protected] Fall Semester 2024-2025 1  Immunodeficiencies and Autoimmunity (CLO4) At the end of this session you will be able to understand: Primary Immunodeficiencies of lymphoid lin...

Immunology II BMS44210A Dr. Afsheen Raza [email protected] Fall Semester 2024-2025 1  Immunodeficiencies and Autoimmunity (CLO4) At the end of this session you will be able to understand: Primary Immunodeficiencies of lymphoid lineage B-cell, T-cell and combined T and B cells immunodeficiency disorders Primary Immunodeficiencies of the Myeloid Lineage Testing for Primary Immunodeficiencies Treatment of Primary Immunodeficiencies 2  Immunodeficiencies and Autoimmunity The immune system is subject to failure of some or all of its parts. This failure can have unwanted results When the system loses its sense of self and begins to attack host cells and tissues, the result is autoimmunity When the system fails to protect the host from disease-causing agents or from malignant cells, the result is immunodeficiency 3 Immunodeficiencies 4  Immunodeficiencies A condition resulting from a genetic or developmental defect in the immune system is called a primary immunodeficiency. In such a condition, the defect is present at birth. This defect may not manifest itself until later in life Secondary immunodeficiency, or acquired immunodeficiency is the loss of immune function and results from exposure to various agents. The most common secondary immunodeficiency is acquired immunodeficiency syndrome, or AIDS, which results from infection with the human immunodeficiency virus 1 (HIV-1) 5 Primary Immunodeficiencies 6  Primary Immunodeficiencies A primary immunodeficiency may affect either adaptive or innate immune functions In adaptive immunodeficiencies, components of adaptive immunity, such as T or B cells are involved In innate immunodeficiencies, components of the innate system, such as phagocytes or complements, are impaired 7  Primary Immunodeficiencies Most defects that lead to immunodeficiencies affect either lymphoid and myeloid cells The lymphoid cell disorders may affect T cells, B cells, or, in combined immunodeficiencies, both B and T cells The myeloid cell disorders affect cells with phagocytic function 8 Recall- Lymphoid or Myeloid Lineages 9 9/1/2024  Primary Immunodeficiencies Most of the primary immunodeficiencies are inherited, and the molecular variations and the genetic defects that lead to these deficiencies have been determined In addition, there are immunodeficiencies that arise from developmental defects (meaning defect during embryogenesis) that impair proper function of an organ of the immune system 10 Types of Primary Immunodeficiencies 11  Primary Immunodeficiencies The defects induced by the primary immunodeficiency depend on the number and type of immune system components involved Defects early in the hematopoietic developmental scheme affect the entire immune system For example, reticular dysgenesis, a stem-cell defect that affects the maturation of all leukocytes; the resulting general failure of immunity leads to susceptibility to infection by a variety of microorganisms Without aggressive treatment, the affected individual usually dies young from severe infection 12  Primary Immunodeficiencies In the case of defective phagocytic function, the major consequence is susceptibility to bacterial infection Defects in more highly differentiated compartments of the immune system have consequences that are more specific and usually less severe For example, an individual with selective IgA deficiency may only be troubled by a greater than normal susceptibility to infections of the respiratory and genitourinary tracts but otherwise leads a normal life without any disorders 13 Primary lymphoid Immunodeficiencies (B-cell immunodeficiency disorders) 14  B-cell immunodeficiency disorders B-cell immunodeficiency disorders can cause various spectrum of diseases due to : complete absence of mature recirculating B cells, plasma cells, and immunoglobulins OR selective absence of only certain classes of immunoglobulins 15  B-cell immunodeficiency disorders Patients with these disorders usually get recurrent bacterial infections but display normal immunity to most viral and fungal infections, because the T cell branch of the immune system is unaffected Most common in patients with humoral immunodeficiencies are infections by encapsulated bacteria as staphylococci, streptococci, and pneumococci because opsonization and clearance of these organisms is dependent on antibodies 16  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA): A B-cell defect called X-linked agammaglobulinemia (XLA) or Bruton’s hypogammaglobulinemia is characterized by: extremely low IgG levels and absence of other immunoglobulin classes 17  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA): In XLA, there is a defect in B-cell signal transduction due to a defect in a transduction molecule called Bruton’s tyrosine kinase (Btk) The BTK gene provides instructions for making the BTK protein, which is important for the development of B cells and normal functioning of the immune system 18  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA): Mutations in the BTK gene prevents production of any BTK protein and absence of functional BTK protein blocks B cell development B cells in the XLA patient remain in the pre-B stage or immature stage and leads to a lack of antibodies Without antibodies, the immune system cannot properly respond to prevent infections 19  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA) B cells in the XLA patient remain in the pre-B stage and lead to a lack of antibodies 20 X-LINKED AGAMMAGLOBULINEMIA (XLA) B cells in the XLA patient remain in the pre-B stage and lead to a lack of antibodies 21  Recall- Pro and Pre-B cells B-cell development begins as lymphoid stem cells differentiate into distinctive B-lineage cell—the progenitor B cell (pro-B cell)—which expresses a transmembrane tyrosine phosphatase called CD45R Pro-B cells proliferate within the bone marrow, and are differentiated into precursor B cells (pre-B cells) The Pre-B cells undergo proliferation and differentiation with the help of bone-marrow stromal cells within the microenvironment 9/1/2024 22  Recall- Progenitor B Cells Proliferate in Bone Marrow 9/1/2024 23  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA) This condition is inherited in an X-linked recessive pattern and occurs exclusively in males The gene associated with this condition is located on the X chromosome In males (who have only one X chromosome), mutation in one copy of the gene in each cell is sufficient to cause the condition In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females 24 B-cell immunodeficiency disorders 25  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA) Children with XLA are usually healthy for the first 1 or 2 months of life because they are protected by antibodies acquired before birth from their mother. After this time, the maternal antibodies are cleared from the body, and the affected child begins to develop recurrent infections Children with XLA generally take longer to recover from infections, and infections often occur again, even in children who are taking antibiotic medications. A palliative treatment for this condition is periodic administration of immunoglobulin, but patients seldom survive past their teens 26  B-cell immunodeficiency disorders X-LINKED AGAMMAGLOBULINEMIA (XLA) The most common bacterial infections that occur in people with XLA are lung infections (pneumonia and bronchitis) ear infections (otitis) pink eye (conjunctivitis) sinus infections (sinusitis) chronic diarrhea Recurrent infections can lead to organ damage 27 B-cell immunodeficiency disorders 28 Primary lymphoid Immunodeficiencies (T-cell immunodeficiency disorders) 29  T-cell immunodeficiency disorders Because of the central role of T cells in the immune system, a T-cell deficiency can affect both the humoral and the cell-mediated responses The impact on the cell-mediated system can be severe, with a reduction in both delayed-type hypersensitive responses and cell-mediated cytotoxicity 30  T-cell immunodeficiency disorders Defects in the cell mediated or T cells system are associated with increased susceptibility to viral, protozoan, and fungal infections Intracellular pathogens such as Candida albicans, Pneumocystis carinii, and Mycobacteria occur often due to the inability of T cells in eliminating intracellular pathogens Infections with viruses (that are rarely pathogenic for the normal individual such as cytomegalovirus or even an attenuated measles vaccine) may be life threatening for those with impaired cell-mediated immunity 31  T-cell immunodeficiency disorders Defects that cause decreased T-cell counts generally also affect the humoral system, because of the requirement for CD4 (T helper) cells in B-cell activation Generally there is some decrease in antibody levels, particularly in the production of specific antibody after immunization 32  T-cell immunodeficiency disorders IMMUNE DISORDERS INVOLVING THE THYMUS Several immunodeficiency syndromes are due to failure of the thymus to undergo normal development Thymic malfunction has a huge effect on T-cell function; all populations of T cells, including helper, cytolytic, and regulatory cells are affected Immunity to viruses and fungi is especially compromised in those suffering from these conditions 33  T-cell immunodeficiency disorders IMMUNE DISORDERS INVOLVING THE THYMUS DiGeorge syndrome, or congenital thymic aplasia, in its most severe form is the complete absence of a thymus This developmental defect is associated with deletion in the embryo of a region on chromosome 22 (22q11.2 deletion), causing immunodeficiency along with characteristic facial abnormalities, hypoparathyroidism, and congenital heart disease 34  T-cell immunodeficiency disorders IMMUNE DISORDERS INVOLVING THE THYMUS 35  T-cell immunodeficiency disorders IMMUNE DISORDERS INVOLVING THE THYMUS The immune defect includes a profound depression of T-cell numbers and absence of T-cell responses Although B cells are present in normal numbers, affected individuals do not produce antibody in response to immunization with specific antigens Thymic transplantation is of some value for correcting the T-cell defects, but many DiGeorge patients have such severe heart disease that their chances for long-term survival are poor, even if the immune defects are corrected 36  T-cell immunodeficiency disorders IMMUNE DISORDERS INVOLVING THE THYMUS 37  Primary lymphoid Immunodeficiencies (Combined T and B-cell immunodeficiency disorders) 38  Combined T and B-cell immunodeficiency disorders Combined deficiencies of the humoral and cell-mediated branches are the most serious of the immunodeficiency disorders The onset of infections begins early in infancy, and the prognosis for these infants is early death unless therapeutic intervention reconstitutes their defective immune system 39  Combined T and B-cell immunodeficiency disorders SEVERE COMBINED IMMUNODEFICIENCY (SCID) SCID disorder involves defects in lymphoid development that affect either T cells or both T and B cells All forms of SCID have common features despite differences in the underlying genetic defects Clinically, SCID is characterized by a very low number of circulating lymphocytes 40  Combined T and B-cell immunodeficiency disorders SEVERE COMBINED IMMUNODEFICIENCY (SCID) There is a failure to mount immune responses mediated by T cells The thymus does not develop, and the few circulating T cells in the SCID patient do not respond to stimulation indicating that they cannot proliferate in response to antigens Myeloid and erythroid (red blood-cell precursors) cells appear normal in number and function, indicating that only lymphoid cells are depleted in SCID 41  Combined T and B-cell immunodeficiency disorders CAUSES OF SEVERE COMBINED IMMUNODEFICIENCY (SCID) SCID may result from defects in (1) the recombination-activating genes (RAG-1and-2) required for synthesis of the functional immunoglobulins and T-cell receptors that characterize mature B and T cells (2) the chain of receptors for IL-2, 4, 7, 9, and 15 (IL-Rγ) and JAK-3, which transduces signals from the gamma chain of the cytokine receptor (3) expression of the class II MHC molecule (4) CD40Ligand. This defect blocks normal maturation of B cells 42 Combined T and B-cell immunodeficiency disorders 43  Combined T and B-cell immunodeficiency disorders SEVERE COMBINED IMMUNODEFICIENCY (SCID) SCID results in severe recurrent infections and is usually fatal in the early years of life. Although both the T and B lineages may be affected, the initial manifestation of SCID in infants is almost always infection by agents, such as fungi or viruses, that are normally dealt with by T-cell immunity The B-cell defect is not evident in the first few months of the affected infant’s life because antibodies are passively obtained from transplacental circulation or from mother’s milk 44  Combined T and B-cell immunodeficiency disorders SEVERE COMBINED IMMUNODEFICIENCY (SCID) SCID infants suffer from chronic diarrhea Pneumonia skin, mouth, and throat lesions opportunistic infections The immune system is so compromised that even live attenuated vaccines (such as the polio vaccine) can cause infection and disease 45  Combined T and B-cell immunodeficiency disorders SEVERE COMBINED IMMUNODEFICIENCY (SCID) The life span of a SCID patient can be prolonged by preventing contact with all potentially harmful microorganisms, for example by confinement in a sterile atmosphere (bubble isolator). However, extraordinary effort is required to prevent direct contact with other persons and with unfiltered air; any object, including food, that comes in contact with the sequestered SCID patient must first be sterilized. Such isolation is feasible only as a temporary measure, pending treatment 46  Primary lymphoid Immunodeficiencies (Immunodeficiencies of the Myeloid Lineage) 47  Immunodeficiencies of the Myeloid Lineage Defects in the myeloid cell lineage affect the innate immune functions Most of these defects result in impaired phagocytic processes that result in recurrent microbial infection of greater or lesser severity There are several stages at which the phagocytic processes may be faulty such as cell motility adherence to and phagocytosis of organisms killing by macrophages 48  Immunodeficiencies of the Myeloid Lineage Quantitative deficiencies in neutrophils can range from an almost complete absence of cells, called agranulocytosis, to a reduction in the concentration of peripheral blood neutrophils below 1500/mm3 called granulocytopenia or neutropenia These quantitative deficiencies may result from congenital defects or may be acquired through extrinsic factors 49  Immunodeficiencies of the Myeloid Lineage Congenital neutropenia is due to a genetic defect that affects the myeloid progenitor stem cell; it results in reduced production of neutrophils during hematopoiesis In 50%–60% of cases, severe congenital neutropenia (SCN) is due to an autosomal dominant ELANE gene mutation. Other mutations are also involved In congenital agranulocytosis, myeloid stem cells are present in the bone marrow but rarely differentiate beyond the promyelocyte stage 50  Immunodeficiencies of the Myeloid Lineage SCN= Severe Congenital Neutropenia 51  Primary lymphoid Immunodeficiencies (Immunodeficiencies of the Myeloid Lineage) Congenital neutropenia 52  Immunodeficiencies of the Myeloid Lineage As a result, children born with this condition show severe neutropenia, with counts of less than 200 neutrophils/mm3 These children suffer from frequent bacterial infections beginning as early as the first month of life; normal infants are protected at this age by maternal antibody as well as by innate immune mechanisms, including neutrophils This genetic defect results in decreased production of granulocyte colony stimulating factor (G-CSF) resulting in a failure of the myeloid stem cell to differentiate along the granulocytic lineage 53  Immunodeficiencies of the Myeloid Lineage Neutrophils have a short life span, and their precursors must divide rapidly in the bone marrow to maintain levels of these cells in the circulation For this reason, agents such as radiation and certain drugs (e.g., chemotherapeutic drugs) that specifically damage rapidly dividing cells are likely to cause neutropenia Occasionally, neutropenia develops in autoimmune diseases as systemic lupus erythematosus; in these conditions, autoantibodies destroy the neutrophils 54 Testing for Primary Immunodeficiencies 55  Testing for Primary Immunodeficiencies Low or normal absolute lymphocyte count on a simple complete blood count and differential and, in some cases, an absent thymic shadow on chest x-ray The diagnosis of severe combined immunodeficiency is confirmed by the findings of either of the following: very low or absent T-cell counts with impaired T-cell function, as measured by assessing the proliferation of T cells in response to stimuli; or maternal engraftment, defined by the presence of maternal T cells in the infant’s circulation 56 Screening Test for SCID: T-cell Receptor Excision Circles T-cell receptor excision circles (TREC) are small circular DNA molecules formed during differentiation of T cells developing in the thymus TREC DNA circles are measured in the blood by polymerase chain reaction (PCR) Normal infant blood samples have one TREC per 10 T-cells, reflecting the high rate of new T-cell generation early in life. Infants with SCID lack TREC altogether 57 Screening Test for SCID: T-cell Receptor Excision Circles 58 Treatment of Primary Immunodeficiencies 59  Treatment of Primary Immunodeficiencies For disorders that impair antibody production, the treatment is administration of the missing protein immunoglobulin Pooled human gamma globulin given either intravenously or subcutaneously protects against recurrent infection in many types of immunodeficiency Maintenance of reasonably high levels of serum immunoglobulin (5 mg/ml serum) will prevent most common infections. 60  Treatment of Primary Immunodeficiencies Treatment options for the immunodeficiencies include replacement of : missing protein missing cell type or lineage missing or defective gene 61  Treatment of Primary Immunodeficiencies Cloning genes that encode immunologically important proteins, such as cytokines, and to express these genes in vitro, using bacterial or eukaryotic expression systems. The availability of such proteins allows these immunologically important proteins to be replaced or their concentrations increased in the patient For example, the administration of recombinant adenosine deaminase has been successfully administered to adenosine deaminase deficient SCID patients 62  Treatment of Primary Immunodeficiencies Therapeutic options in ADA-SCID and reported autoimmune manifestations after treatment 63  Treatment of Primary Immunodeficiencies Bone-marrow transplantation is the replacement of stem cells of the patient with those from an immunocompetent donor (Usually a HLA compatible sibling) The basic principle for bone marrow transplant is that CD34+ progenitor cells (CD34 is specific for human hematopoietic stem/progenitor cells (HSPCs) are harvested from the patient's bone marrow or after mobilization in the circulation), transduced (converted) ex vivo with a viral vector with the correct gene, and then reinfused into the patient It allows development of a functional immune system. High rates of success have been reported for those who get an HLA-identical donor 64 Treatment of Primary Immunodeficiencies 65 66