Primary and Secondary Immunodeficiency

Secondary (acquired)

-a variety of drugs, cancers, or infectious agents can results in acquired immunodeficiencies -many viruses are capable of infecting and killing lymphocytes, lowering the immune response

Severe combined immunodeficiency

-(SCID, pronounced "skid") is a rare syndrome of diverse genetic causes in which there is combined absence of T lymphocyte and B-lymphocyte function. In many cases, there is also absence of natural killer, or NK, lymphocyte function

Cancer cells

-A cell becomes cancerous when it undergoes transformation and begins to proliferate without control. The surfaces of tumor cells acquire tumor-associated antigens that mark them as nonself to the immune system. This figure illustrates the attack on such a cancer cell by activated CD8+ T cells (CTLs) -Activated macrophages can also destroy cancer cells. -While a healthy immune system serves to prevent most cancers, it has limitations. In some cases there is no antigenic epitope for the immune system to target. -Tumor cells can even reproduce so rapidly that they exceed the capacity of the immune system to deal with them. -Finally, if the tumor cell begins reproducing in tissues and becomes vascularized (connected to the body's blood supply), it usually becomes invisible to the immune system

superantigens

induce polyclonal T cell activation, inhibiting antigen-specific immunity

first major problem with IgA deficiency

-A common problem in IgA deficiency is susceptibility to infections. -Recurrent ear infections, sinusitis, bronchitis and pneumonia are the most common infections seen in patients with Selective IgA Deficiency. This is easy to understand because IgA protects mucosal surfaces from infections. -These infections may become chronic. Furthermore, the infection may not completely clear with treatment, and patients may have to remain on antibiotics for longer than usual.

DiGeorge Syndrome

-A primary immune deficiency disease which is caused by abnormal development of certain cells and tissues of the neck during growth and differentiation of the fetus. -The region of the developing embryo that is affected in the DiGeorge Syndrome controls the development of the face, parts of the brain, the thymus, the parathyroid glands, the heart and the aorta -Patients with the DiGeorge Syndrome may have defects in their T-lymphocyte function, and as a result, they have an increased susceptibility to viral, fungal and bacterial infections -As with the other defects in the DiGeorge Syndrome, the T- lymphocyte defect varies from patient to patient. In addition, small or mild deficiencies may disappear with time

Secondary major problem with IgA deficiency

-A second major problem in IgA deficiency is the occurrence of autoimmune diseases. -In autoimmune diseases an individual produces antibodies or T- lymphocytes which react with his/her own tissues with resulting damage to these tissues. -Some of the more frequent autoimmune diseases associated with IgA deficiency are: Rheumatoid Arthritis, Systemic Lupus Erythematosis and Immune Thrombocytopenic Purpura (ITP). -These autoimmune diseases may cause sore and swollen joints of the hands or knees, a rash on the face, anemia (a low red blood cell count) or thrombocytopenia (a low platelet count). Other kinds of autoimmune disease may affect the endocrine system and/or the gastrointestinal system

Several therapeutic cancer vaccines are being tested in human trials. There are 2 primary approaches to making a cancer vaccine: whole-cell vaccines and antigen-type vaccines

-A whole-cell vaccine is prepared from cancer cells taken from a patient's tumor or from tumor cell lines in laboratory collections. These cells need to be altered to inactivate them for safety. -Antigen-type vaccines attempt to trigger an immune response to antigens that are found on cancer cells. Such antigens might be from a specific cancer on an individual or to antigens found on several types of cancer

Some of the immune abnormalities in HIV infection include:

-Altered cytokine expression -Decreased CTL and NK cell function -Decreased humoral and proliferative response to antigens and mitogens -Decreased MHC-II expression -Decreased monocyte chemotaxis -Depletion of CD4+ cells Impaired DTH reactions -Lymphopenia -Polyclonal B-cell activation

The Prevention and Treatment of AIDS pt. 2

-Available drugs delay the progress of the HIV infection, not a cure! -Chemotherapy can inhibit HIV replication & delay CD4+ decline. -The rapid reproductive rate and frequent occurrence of drug-resistant mutations dictates that multiple drugs, given simultaneously, must be used. The current treatment is termed highly active antiretroviral therapy (HAART). This therapy consists of administering drug combinations. -Patients are often required to take as many as 40 pills a day on a complex schedule, which must be adhered to rigorously because the virus is unforgiving -An important consideration for HIV vaccine development is the fact that the immune system has not shown much capability in coping with natural infections. -Obstacles to the development of a vaccine for HIV are formidable many unsuccessful vaccine trials. -The HIV virus has a rapid mutation ratedifficult to develop a vaccine that is effective against all mutational virus variants. -The HIV virus has developed variants that differ substantially from one geographic area to another, and each would probably require an appropriate vaccine

The Prevention and Treatment of AIDS

-Education programs to: >promote the use of condoms >discourage sexual promiscuity >prevent the use of contaminated needles among IDUs -Much progress has been made in the use of chemotherapy to slow down HIV replication and thus they delay the decline of CD4+ T cells. -Available drugs only delay the progress of the infection, they are not a cure. -One clearly successful application of chemotherapy has been to reduce the chance of HIV transmission from an infected mother to her newborn. The administration of even one nucleoside reverse transcriptase drug alone reduces the incidence. -In the absence of treatment, the transmission rate between the mother and child is 25%. -When drug treatment and Caesarian section are used, the rate of transmission can be reduced to 1%

Another approach for using the immune system against cancer is to try to stimulate the immune system in a more general way

-For example, to mix dendritic cells (researchers have found ways to dramatically increase their numbers) with genetic material from a tumor. -Hopefully, these dendritic cells will then efficiently present the cancer antigens to cytotoxic cells of the immune system. -Although work with potential cancer vaccines has been in progress for almost a century, it is an area that should be considered to be in only an early stage. -Currently, a cancer vaccine would probably be most useful at preventing recurrences after other forms of treatment because the immune system would have to deal with a smaller number of cells.

There are over 150 different primary immunodeficiency diseases and they affect people differently

-For some, the body fails to produce any or enough antibodies to fight infection, while for others; the cellular defenses against infection fail to work properly. -Throughout their lives, people with primary immunodeficiencies are more susceptible to infections, endure recurrent health problems and often develop serious and debilitating illnesses.

signs and symptoms of primary immunodeficiency can include

-Frequent and recurrent ear infections, pneumonia, meningitis, bronchitis, sinus infections or skin infections -Blood infections -Inflammation and infection of internal organs (ex: liver) -Blood disorders, such as low platelet counts or anemia -Digestive problems: cramping, loss of appetite, nausea and diarrhea -Delayed growth and development -Autoimmune disorders

HIV evades host immune response by rapid mutation

-HIV and other retroviruses have error-prone reverse transcriptases, generating mutant variant viruses or quasi-species -Selection of mutant viruses that have lost the epitope recognized by the host immune system -Sometimes, homologous peptides of variant viruses interfere the presentation of the original peptides -Such diversity greatly complicates vaccine development and limits the effectiveness of anti- viral drug

SCID

-Intravenous immunoglobulin (IVIG) replacement therapy should be given to SCID infants. Although IVIG will not restore the function of the deficient T-lymphocytes, it does replace the missing antibodies resulting from the B-lymphocyte defect. -For patients with SCID due to ADA deficiency, replacement therapy with a modified form of the enzyme (called PEGADA) has been used with success. However, this immune reconstitution is not a permanent cure and requires subcutaneous injections for the rest of the child's life. -The most successful therapy for SCID is immune reconstitution by bone marrow or cord blood transplantation.

Concept of Immune Surveillance

-It was postulated that the cell-mediated immune system probably arose to combat cancer cells and that the appearance of a cancerous growth represented a failure of the immune system. -This concept has been supported by the observation that cancers occur most often in older adults, whose immune systems are becoming less efficient, or in the very young, whose immune systems may not have developed fully or properly. -Also, individuals who are immunosuppressed by either natural or artificial means are more susceptible to certain cancers

CVID diagnosing

-Most individuals with CVID present first with recurrent bacterial infections and, when tested, have markedly decreased serum immunoglobulin levels and impaired antibody responses. -Studies on the cells of the immune system in patients with CVID have revealed a spectrum of lymphocyte abnormalities (cause unknown). • Most patients appear to have normal numbers of B-lymphocytes, but they fail to undergo normal maturation into plasma cells capable of making the different types of immunoglobulins and antibodies. • Other patients lack the helper T-lymphocytes necessary for a normal antibody response. A third group of patients have excessive numbers of cytotoxic T-lymphocytes.

HIV causes AIDS

-Someone can be HIV infected and yet not show the AIDS symptoms. The HIV infected phase can last >10 years. Some people can leave this HIV infected phase for less than 5 years (2 years example) and some can leave 15 years. -Someone who has AIDS is someone who is infected with HIV and at the terminal phase of his infection when opportunistic diseases develop because of the failure of the immune system. These diseases will be then responsible of the death of the patient.

symptoms of CV immunodeficiency

-The clinical signs/symptoms vary from severe to mild. -Frequent and unusual infections may occur first during early childhood, adolescence or adult life. -In the majority of patients, however, the diagnosis is not made until the 3rd or 4th decade of life.

cancer cure

-The hypothesis that cancer represents a failure of the immune system has led to the thought that the immune system might be used to prevent or cure cancer—that is, immunotherapy. -Cancer vaccines might be either therapeutic (used to treat existing cancers) or prophylactic (to prevent the development of cancer). -Actually, prophylactic vaccines already exist—indirectly. -Hepatitis B virus is a common cause of liver cancer and a vaccine against infection by this virus is widely used. -HPV has recently been added to this list.

The only "permanent cure" for Wiskott-Aldrich Syndrome is a bone marrow transplantation or cord blood stem cell transplantation

-The oldest bone marrow transplanted patients are now in their twenties and thirties and seem to be cured, without developing malignancies or autoimmune diseases. -Because patients with Wiskott-Aldrich Syndrome have some residual T- lymphocytes function in spite of their immune deficiency, immunosuppressive drugs and/or total body irradiation are required to condition the patient before transplantation. -If the affected boy has healthy siblings with the same parents, the entire family should be tissue typed to determine whether there is an HLA-identical sibling (a good tissue match) who could serve as bone marrow transplant donor. • The results with HLA identical sibling donor bone marrow transplantation in WAS are excellent with an overall success (cure) rate of 80-90%. • The success rate of MUD transplants decreases with age and the decision to transplant teenagers or adults with WAS may be difficult.

SCID: Deficiency of the alpha chain of the IL-7 receptor

-This form of SCID is due to mutations in a gene on chromosome 5 that encodes a component of another T- lymphocyte growth factor receptor, the alpha chain of the IL-7 receptor. -Infants with this type of SCID have B- and NK- lymphocytes but no T-lymphocytes; the B-lymphocytes don't work because of the lack of T-lymphocytes. -This form of SCID is inherited as an autosomal recessive trait. IL-7 receptor deficiency is seen in less than 5% of SCID cases

SCID: Deficiency of Janus kinase 3

-This type of SCID is caused by a mutation in a gene on chromosome 19 that encodes an enzyme called Janus kinase 3 (Jak3). -This enzyme is necessary for function of the above-mentioned common gamma chain. -Infants with this form of SCID have the same kinds of T, B and NK-lymphocyte counts as those with X-linked SCID. -However, this form of SCID is inherited as an autosomal recessive trait. Thus, both boys and girls can be affected. Jak3 deficiency accounts for less than 10% of all cases of SCID

SCID: Deficiency of Adenosine Deaminase

-This type of SCID is caused by mutations in a gene on chromosome 20 that encodes an enzyme called adenosine deaminase (ADA) that is essential for the metabolic function of a variety of body cells, but especially T-lymphocytes. -The absence of this enzyme leads to an accumulation of toxic metabolic by-products within lymphocytes that cause them to die. -ADA deficiency accounts for approximately 15% of cases of SCID. Babies with this type of SCID have the lowest total lymphocyte counts of all, with T, B and NK-lymphocyte counts all being very low. This form of SCID is inherited as an autosomal recessive trait

SCID: Deficiency of Recombinase Activating Genes

-This type of SCID is due to mutations in genes on chromosome 11 that encode enzymes necessary for the development of the antigen recognition receptors on T and B- lymphocytes. -These genes are called recombinase activating genes 1 and 2 (RAG1 and RAG2). -Infants with this type of SCID lack T- and B-lymphocytes but have NK-lymphocytes. -This form of SCID is inherited as an autosomal recessive trait

third major problem with IgA deficiency

-allergies (food allergies and severe, unresponsive asthma, but not typically seasonal allergies such as hay fever) may also be more common among individuals with Selective IgA Deficiency than among the general population. -Another unusual, but important, form of allergy may also occur in IgA deficiency. In people whose blood contains no IgA, IgA from other individuals may be recognized by the immune system as a foreign protein. -Because antibodies are normally made against foreign proteins, some people with Selective IgA Deficiency make an IgG or IgE antibody against IgA. In this situation, if an IgA deficient person who has antibodies against IgA receives a blood product that contains IgA, an allergic reaction may result.

causes of acquired immunodeficiency

-cancer -cytotoxic drugs or radiation -malnutrition -splenectomy -immunosuppressive therapies -stress/emotions -aging -infection

MAB's for cancer

-monoclonal antibodies are a promising tool for delivering cancer treatment. -A humanized monoclonal antibody, Herceptin is currently being used to treat a form of breast cancer. -Herceptin specifically neutralizes a genetically determined growth factor, HER2, that promotes the proliferation of the cancer cells. It is expressed in relatively high quantities in about 25 to 30% of breast cancer patients. -another approach that makes use of monoclonal antibodies is to combine a monoclonal antibody with a toxic agent, forming an immunotoxin. -Theoretically, an immunotoxin might be used to specifically target and kill cells of a tumor with little damage to healthy cells. -There have been some promising results in clinical trials but not with large tumor masses where many of the tumor cells cannot be reached by the immunotoxin

Disorders Associated with the Immune System

-not all immune system responses produce a desirable results -one's own tissue may be mistakenly attacked by the immune system, causing diseases we classify as autoimmune -some people are born with a defective immune system -disease can also impair the immune system (HIV) -our immune systems can be "deliberately crippled" (immunosuppressed) to prevent the rejection of transplanted organs -plus, in all of us, the effectiveness of our immune system declines with age

origins of immunodeficiency

-primary (congenital) ◦Inherited genetic defects in immune cell development or function ◦ Inherited deficiency in a particular immune molecule -secondary (acquired) immunodeficiency ◦ A loss of previously functional immunity due to: Infection, toxicity, radiation, splenectomy, aging, malnutrition, cancer, viral infections, etc.

Wiskott-Aldrich Syndrome

-primary immune deficiency disease involving both T- and B-lymphocytes. -Platelets (helps control bleeding) are also affected. -In its classic form, the WAS has a characteristic symptoms: 1) an increased tendency to bleed caused by a reduced # platelets 2) recurrent bacterial, viral and fungal infections 3) eczema of the skin. -In addition, long term observations of patients with the WAS have revealed an increased incidence of malignancies, including lymphoma and leukemia, and an increased incidence of autoimmune diseases in some patients. • Although it remains a serious disease in which life threatening complications may occur, many affected males go through puberty and enter adulthood, live productive lives and have families of their own.

Ataxia-Telangiesctasia

-primary immunodeficiency disease which affects a number of different organs in the body • Neurologic abnormalities resulting in an unsteady gait (ataxia) • Dilated blood vessels (telangiectasia) of the eyes and skin. • A variable immunodeficiency involving both cellular (T- lymphocyte) and humoral (B-lymphocytes) immune responses. • A predisposition to certain kinds of cancer (particularly of the immune system, such as lymphoma & leukemia)

Complement Deficiencies

-single component deficiencies -hereditary angioedema -C5, C6, C7, C8, or C9 deficiency

Primary (congenital) immunodeficiency

-some people are born with a defective immune system -defects in, or the absence of, a number of inherited genes can result in congenital immunodeficiencies

SCID: Deficiency of the common gamma chain of T-lymphocyte receptors for growth factors

-the most common form of SCID, ~45% of all cases. -It is due to mutations in a gene on the X chromosome that encodes a component (or chain) shared by receptors for growth factors on the surface of T-lymphocytes and NK-lymphocytes. This component is necessary for normal growth and function of T-lymphocytes. -This form of SCID is inherited as an X-linked recessive trait. Thus, only males have this type of SCID. -Mutations in this gene result in very low T-lymphocyte and NK- lymphocyte counts, but the B-lymphocyte count is normal. Despite the normal number of B-lymphocytes, there is poor B-lymphocyte function

AIDS

acquired: because it is a condition that has to be contracted. It cannot be inherited or transmitted through the genes immune: because it affects the body's immune system, the part of the body that fights off diseases deficiency: because it makes the immune system stop working properly syndrome: because people with AIDS experience a number of different symptoms and opportunistic diseases -when HIV infection becomes advanced it often is referred to as AIDS. AIDS generally occurs when the CD4 (helper T cell) count is below 200/ml

Symptoms of opportunistic infections common in people with AIDS include:

• Coughing and shortness of breath • Seizures and lack of coordination • Mental symptoms such as confusion and forgetfulness • Severe and persistent diarrhea • Vision loss • Nausea, abdominal cramps, and vomiting • Weight loss and extreme fatigue • Severe headaches • Fever • Coma

five currently known genetic types of SCID

• Deficiency of the common gamma chain of T-lymphocyte receptors for growth factors • Deficiency of Janus kinase 3 • Deficiency of the alpha chain of the IL-7 receptor • Deficiency of Adenosine Deaminase • Deficiency of Recombinase Activating Genes

primary immunodeficiency diseases (PIDD)

• First recognized ~50 years ago • Rate lower than CF (1:2500) in Caucasians but comparable to (phenylketonuria) PKU (1:10,000) • Some are rare • Some are common, like IgA deficiency and common variable immunodeficiency • Adaptive, innate, lymphocyte development, etc •First recognized ~50 years ago •X-linked agammalobulinemia was the first immunodeficiency to be identified - 1952 Colonel Ogden Bruton described an 8 yr old boy with recurrent life threatening infections (pneumonia, septicemia, etc.) from age 2 - Challenges with antigens showed no antibody development

HIV: why is it formidable

• High mutability and slow progression: >Changes in viral antigens (immune targets); and enzymes (drug targets) >Generation of viral variants >Difficult to make vaccines >High rates of vertical and lateral transmissions • Targets CD4 T cells • One HIV drug is effective transiently. • Combination therapy using multiple drugs are more effective

Paitents with X-Linked Agammaglobulinemia (XLA) are prone to develop infections because they lack antibodies

• Infections may also penetrate the mucosal surface, invade the bloodstream and spread to other organs deep within the body, such as the bones, joints or brain. Infections in XLA patients are usually caused by microorganisms that are killed or inactivated very effectively by antibodies in normal people. • The most common bacteria that cause infection are the pneumococcus, Streptococcus, Staphylococcus andHemophilus influenzae. Some viruses may also cause serious infections in these patients

AIDS is characterized by the appearance of opportunistic infections. These are infections that take advantage of a weakened immune system and include:

• Pneumocystis carinii pneumonia• Malignancies (lymphoma, cervical cancer & Kaposi's Sarcoma) • Toxoplasmosis• Tuberculosis• Extreme weight loss & wasting; exacerbated by diarrhea• Meningitis and other brain infections• Fungal infections

Selective IgA deficiency is the most common primary immunodeficiency disease.

• Studies have indicated that as many as one in every five hundred people have selective IgA deficiency. • IgA deficiency may be inherited as either an autosomal dominant (requiring only one parent to pass down the defective gene) or recessive (requiring defective genes from both parents) trait. •Individuals with Selective IgA deficiency do not produce IgA. • They do, however, produce all the other immunoglobulin classes. In addition, the function of their T-lymphocytes, phagocytic cells and complement system are normal or near normal. Hence, this condition is known as "Selective" IgA deficiency

Many have relatively mild illnesses and are generally not sick enough to be seen by a doctor (don't know are IgA deficient)

• The majority of individuals with Selective IgA Deficiency are relatively healthy and free of symptoms. • There are also individuals with Selective IgA Deficiency who have significant illnesses. • Currently, it is not understood why some individuals with IgA deficiency have almost no illness while others are very sick.

X-linked Agammaglobulinemia

• X-Linked Agammaglobulinemia (XLA) was first described in 1952 by Dr. Ogden Bruton. This disease, sometimes called Bruton's Agammaglobulinemia or Congenital Agammaglobulinemia, was one of the first immunodeficiency diseases to be identified. • XLA is an inherited immunodeficiency disease in which patients lack the ability to produce antibodies, proteins that make up the gamma globulin or immunoglobulin fraction of blood plasma. • Currently no cure. The defective gene cannot be repaired or replaced, nor can the maturation process be induced. • Patients can be given some of the antibodies that they are lacking. The antibodies are supplied in the form of gamma globulins (~immunoglobulins) given intravenously.

common variable immunodeficiency

•Characterized by low levels of serum immunoglobulins (antibodies) and an increased susceptibility to infections. • Exact cause of the low serum Ig levels not known • A relatively common form of immunodeficiency, hence, the word "common". • In some patients there is a decrease in both IgG and IgA; in others, all three major types (IgG, IgA and IgM) of immunoglobulins may be decreased. • The degree and type of deficiency of serum immunoglobulins, and the clinical course, varies from patient to patient, hence, the word "variable."